SIK Inhibitors Overview: A Topical Tan Solution to MELANOTAN I/II, Osteogenesis Drug, and Possible Alternative to GLP-1 Medications(MAYOCELS GTFINH)

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Prerequisites to this guide:​

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MOBILE USERS PLEASE USE DESKTOP SITE OPTION IN SETTINGS OR ZOOM OUT It's fucking unreadable if you dont I have NOT tested the Formulations myself found later in the guide please use with discretion First Guide guys formatting and writing all over the place chill on me anyways enjoy reading ​

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Glossary:​

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Explanation of SIK

Melanogenesis Overview & Relation to SIK

SIK Inhibition

Trials & Findings

Topical Formulation

Salt-inducible kinases:​

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Salt-inducible kinases(SIK) Are a family of Serine/threonine Proteins that regulate innumerable cellular processes, including metabolic responses to feeding/fasting(Gluconoeogenesis), cell division and oncogenesis(Initiation of cancer), Osteogenesis(Bone Synthesis), inflammation, sleep and circadian rhythms, along with various other important roles in the endocrine system. the SIK family consists of three members; SIK1, SIK2, and SIK3. Although they share similar structures each perform diverse physiological functions by regulating numerous pathways in the body, and are highly important in overall homeostasis. For the purposes of this guide, the primary focus is SIK2, as it plays a vital role in the regulation of Melanogenesis. ​ ​

TL;DR:
SIK is a family of proteins found in our bodies that regulates lots of stuf including SIK2's regulation of tanning proccess luh bruh



Process of Melanogenesis:​

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Melanogenesis is a complex biological process where Melanocytes(Specialized cells) synthesize two types of melanin, Eumelanin(brown-black) and pheomelanin(yellow-red). Melanin plays a key role in absorbing Ultra-violet Radiation, this limits the damaging effects of UV cellular macromolecules(DNA and RNA put simply) and aids in prevention of photoaging skin. Beyond this important role, the added benefit of Increased Melanin production is it's Aesthetic value in the Looks space. It's generally conceded that a Tan is far more attractive than being pale and signals youth and vitality.​

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The Melanocortin 1 receptor(MC1R) plays an important part of skin pigmentation and acts as response to exposure of Ultraviolet Radiation, once skin is exposed to UV Radiation, MC1R gets stimulated and begins a cascade of signaling. The signaling pathways primarily involved are cAMP, PKA, CREB. These pathways regulate the MITF transcription factor and activation, and controls the expression of Tyrosinase and its related proteins(TYRP-1, TYRP-2), the enzymes responsible for melanin synthesis.​

TL;DR:
melanogenesis is process that make u tan
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Now that you understand the basic overview of Salt-inducible kinases(SIK) and the process of melanin production,
how does SIK2 factor into the regulation of Melanogenesis and what does SIK Inhibition overall mean for Pharmacotherapy?

(nigga holding queef juice)​

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SIK Inhibition:​

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​ click me if hard to read lulz​ click me if hard to read lulz​

To Start, SIK Inhibitors were originally developed to explore the biological functions of the SIK family without the need of Gene Manipulation, A notable Inhibitor like HG-9-91-01 was first deployed to inhibit all three isoforms of the family, with differentiating levels of inhibition, Many others were developed after with the same goal in mind. An interesting use case of a separate SIK inhibitor, specifically YKL-05-099(Derived from HG-9-91-09) in a study was shown to have an effect on osteocytes due to it's higher selectivity through PKA-dependent phosphorylation downregulation(PTH signaling cascade) although more specifically the reduction of HDAC4/5 phosphorlation in osteocytes, as a result downregulating the SOST protein expression in osteocytes, YKL-05-099 also inhibits the CSF1R Receptor for M-CSF inducing appositional growth without increasing osteocytes activity(Bone Resorption). A Similar selective Inhibitor(SK-124), SIK2/3 Inhibitor, was found to be far more Potent than YKL-05-099 in Osteogenesis with the addition of net zero short term toxicity recorded. It works in an analogous approach to YKL-05-099, both suppressing phosphorylation of HDAC4/5 but also CRTC2. For both YKL-05-099 and SK-124 were shown improved bone formation and mass, mimicking PTH1R Signaling of Osteogenesis, although most trials were done in vivo of animals some were done on humans and showed no difference in effects.​ ​ SIK1 and SIK2 both have Important Roles in the Regulation of lipogenesis. SIK1 acts through the inhibition of the sterol regulatory element-binding protein(SREBP-1c), which is a main factor in fatty-acid and triglyceride synthesis, Inhibiting this protein Surpresses the expression of Fatty acid and Acetyl-CoA carboxylase synthesis, using an Inhibitor for this purpose will likely slow the process of fat creation, furthermore SIK Inhibition has potential implications for future Metabolic therapies for fat loss beyond the Current GLP-1 Based agonists I.e (Retatrutide, Semaglutide, Tirzepatide).​ SIK2 Inhibition: In almost all cases of SIK Inhibition cAMP/PKA are present, SIK2 Inhibition in regards to pharmaceutical targeting of Melanin Synthesis is no different, earlier in the thread i mentioned the MC1R regulator and the other important pathways in Melanogenesis, SIK2's role in this system is by directly controlling the activity of cAMP-regulated transcriptional coactivators(CTRCs) and CREB (cAMP response element-binding protein), a key transcription factor. The promotion of these responses enhances the MITF expression sequentially upregulating melanin synthesis(Melanogenesis), In other words, usage of a SIK2 Inhibitor can make you more tan. In former studies Topical SIK2 Inhibitors were unlikely to work effectively as the Outer Skin Barrier in humans are far harder to penetrate than the animal skin used in vivo studies, however one named YKL-06-061 showed more promise than others, eventually recent advancements led to 2nd Generation SIK2 Inhibitors being developed which had far better Penetration Capabilities. Those being: SLT-008 and SLT-001, Moreover usage of said Inhibitors after UV-Based DNA Damage led to promoted tissue repair and collagen protection. The suppression of the MMP-1 enzyme which is a main factor in aging caused by UV Damage, was identified to be present in Both Inhibitors aswell.​ Key:​ Term: Definition: Phosphorylation: phosphorylation noun​ The process of transferring a phosphate group from a donor to an acceptor; often catalysed by enzymes. Parathyroid hormone (PTH): key regulator of bone remodeling, the continuous process of bone resorption and formation. PTH indirectly stimulates osteoclast activity, promoting the release of calcium from the bone matrix to restore serum calcium levels. Appositional Growth: Appositional growth​ Definition noun Growth by forming new layers on the surface of pre-existing layers; process of increasing in thickness rather than length. Supplement In bones, this method of growth is accomplished by the addition of newly formed cartilage on the surface of the previously formed cartilage. The result is growth in diameter rather than in length. ​

Trials & Findings:​

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Study 1(IN VIVO HUMAN):​	Study 2(IN VIVO MICE, EX VIVO HUMAN SKIN):​
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A series of SIK inhibitors featuring a pyrimidine-pyridone pharmacophore have been developed. The incorporated substituents allow for modulation of lipophilicity and physical properties, which, in turn, influence skin penetration. SLT-008 (Figure 1a) is a novel SIK inhibitor with high lipophilicity (clogP 6.66; Property Calculator, Molinspirations, Slovak Republic) and a molecular weight of 577.78. Similarly, SLT-001 (Figure 1B) has a clogP value of 5.2 and a molecular weight of 527.67 The biochemical potencies of SLT-008 and SLT-001 against the three SIK isoforms 1, 2 and 3 were determined with KinaseProfiler™ assays. SLT-008 and SLT-001 exhibited high potency against SIK1/2 and selectivity over SIK3, with IC50 of SIK1/2/3 being 5/8/>20 nM for SLT-008 and 7/14/>20 nM for SLT-001. To confirm their SIK cellular target engagement, a NanoBRET assay was performed. In this assay, engagement with a fluorescent tracer molecule that binds the ATP-binding site of SIK1 in a NanoLuc-SIK1 fusion leads to a BRET signal. A SIK1-binding ligand displaces the tracer, leading to a diminished signal. SLT-008 and SLT-001 bind to SIK1 strongly with an IC50 of 9.7 and 1.9 nM, respectively. SLT-008, SLT-001 or vehicle (ethanol 70%, propylene glycol 30%) were topically administered to an explant derived from a 67-year-old Caucasian woman (skin phototype II). The application was administered twice, a day before and after UV-B exposure. DNA damage was then assessed 24 h after irradiation. At 24 h post-UV-B exposure, CPD levels were significantly decreased by treatment with SLT-008 (60.1%, Figure 2b,c). Treatment with SLT-001 resulted in an even greater reduction in CPD levels, reaching 93.9%, These findings indicate that SIK inhibitors, such as SLT-001 and SLT-008, effectively reduce UV-induced DNA and tissue damage. Exposure of skin to UV radiation induces upregulation of MMP-1 expression, which leads to the breakdown of collagen, contributing to premature skin ageing (photoageing) [25, 26]. The protective effects of SIK inhibition were further evaluated by measuring MMP-1 levels. Skin explants were treated as outlined in Figure 2a. Following UV-B exposure, MMP-1 levels significantly increased by 139% compared to baseline (Figure 3a,b). Treatment with SLT-008 reduced MMP-1 levels by 52%, while SLT-001 achieved a greater reduction of 78% (Figure 3a,b). No significant reduction was observed with SLT-043 (Figure 3c,d), or with the photolyase treated group. MMP-1 expression was examined immediately after UV-R and 24 h post UV-R. As expected, immediately post UV-R MMP-1 was not induced at the protein level (Figure 5a,b). However, 24 h post-UV-R exposure, a significant induction of MMP1 was observed in the vehicle group in both the epidermis and dermis (Figure 5a indicated by black arrows), with an increase of 77%. In contrast, in the SLT-001 treated group, there was no significant increase In summary, we provide evidence that SIK inhibitors, SLT-001 and SLT-008, offer protection against UV-induced photodamage. Topical application of these cosmetic ingredients represents a powerful approach to mitigate UV-induced damage and photoageing, while potentially delivering broader cosmetic benefits.​ Inbal Rachmin, Le Varlet, B., Regazzetti, C., Thierry Passeron, Wang, J., Fisher, D. E., Philippe Schaison, & Braham Shroot. (2025). A novel approach to target skin photodamage: Topical application of salt inducible kinase inhibitors. International Journal of Cosmetic Science, 48(1), 1–15. https://doi.org/10.1111/ics.70003​	Topical Treatment with HG9-91-01 Causes Robust Darkening that Is Progressive and Reversible in Mc1re/e;K14-SCF Mice (A–D) Shown here: (A) Mc1re/e;K14-SCF mice and Tyrc/c;K14-SCF mice before treatment (day 0) and after 7 days of treatment (day 7) with 30 μL vehicle control (70% ethanol, 30% propylene glycol) or 37.5 mM HG 9-91-01 (image is representative of n = 4 experiments). (B) Reflective colorimetry measurements (L∗ white-black color axis; n = 4, mean ± SEM) and (D) melanin extraction (image is representative of n = 4 experiments) of the Mc1re/e;K14-SCF mice and Tyrc/c;K14-SCF mice described in (A). (C) Skin sections of Mc1re/e;K14-SCF mice described in (A) stained with Fontana-Masson (eumelanin) (top two panels) or H&E (bottom two panels); (magnification, 400×). White arrows represent nuclear capping; scale bar represents 25 μm. (E) Mc1re/e;K14-SCF mice and Tyrc/c;K14-SCF mice before treatment (day 0) and after 6 days of treatment with 30 μL vehicle control (70% ethanol, 30% propylene glycol) or 37.5 mM HG 9-91-01 (day 6), and 40 days post-treatment (day 46) (vehicle mouse in day-46 photo is different from that in the day-0 and day-6 photos). (F and G) Reflective colorimetry measurements (CIE L∗ white-black color axis) of (F) Mc1re/e;K14-SCF mice and (G) Tyrc/c;K14-SCF mice treated as described in (E). Vehicle-treated Mc1re/e;K14-SCF mice: n = 5 (days 0–19), and n = 4 (days 24–34); HG 9-91-01-treated Mc1re/e;K14-SCF mice: n = 3; vehicle-treated Tyrc/c;K14-SCF mice: n = 3 (days 0–10), and n = 2 (days 11–20); HG 9-91-01-treated Tyrc/c;K14-SCF mice: n = 3 (mean ± SEM). For the graph in (B), statistical significance is reported as follows: ∗∗∗∗p < 0.0001, multiple t test analysis with the two-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli. For the graphs in (F) and (G), statistical significance is reported as follows: ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001, two-way ANOVA with Sidak’s multiple comparisons test comparing treatment to vehicle control at each time point. Treatment of human skin explants with passive topical application of the second-generation SIK inhibitors, YKL 06-061 and YKL 06-062, induced significant pigmentation after 8 days of treatment (1×/day), but no significant gross pigmentation was observed in skin treated with HG 9-91-01 (Figure 4A). Fontana-Masson staining revealed increased melanin content in skin treated with YKL 06-061 or YKL 06-062 and marginally increased melanin in skin treated with HG 9-91-01, as compared with control. This effect was reproducible with independent preparations of synthesized drugs applied passively (via pipette) to the top of different human skin explants. Mechanical application of the first-generation SIK inhibitor HG 9-91-01, by rubbing via an applicator, induced significant gross pigmentation , and increased melanin content was observed upon Fontana-Masson staining of skin sections, suggesting that HG 9-91-01’s limited human skin penetration can be, at least partially, overcome through mechanical application. YKL 06-061 and YKL 06-062 did not require mechanical application (rubbing) to induce significant human epidermal darkening. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk.​ Mujahid, Nisma. “(PDF) a UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin.” Research Gate, 13 June 2017, www.researchgate.net/publication/317576045_A_UV-Independent_Topical_Small-Molecule_Approach_for_Melanin_Production_in_Human_Skin.​

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Topical Formulation:
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Spoiler: DISCLAMER PLEASE READ: ANOTHER DISCLAIMER I AM IN NO WAY AN EXPERT ON PHARAMCUETICAL VEHICLES/TOPICAL AGENT DEVELOPMENT, IF YOU PLAN TO DIY PLEASE USE DISCRETION

From all that was gathered from this Guide along with the Studies, the choice for a Topical agent goes down to SLT-001 and SLT-008, both with similar benefits although they differ in Lipophilicity and Molecular weight, which are thing to consider when Formulation is undergoing. SLT-001 was found to be more compatible and had a slightly higher reduction of UV Based Skin Damage, and was optimized solely for Clinical Trials(Human Testing). In my opinion this would be the main choice as it is the most promising and seemingly compatible Topical SIK Inhibitor currently available.​

SLT-001 and SLT-008 Skin Safety Profile:​ Toxicological endpoint OECD TG SLT-001 SLT-008 Skin irritation HRE 439 Non skin irritant Non skin irritant Phototoxicity 3 T3 NRU 498 Non phototoxic Non phototoxic Mutagenicity (Ames) 471 Non mutagenic Non mutagenic Genotoxicity (Micronucleus) 487 Non aneugen and non clastogen Non aneugen and non clastogen Skin sensitization SENS-IL18 NA / Non sensitizer Skin sensitization SENS-IS NA Non sensitizer Non sensitizer Skin sensitization GARD 442E Sensitizer NA

Note: Skin irritation: cytotoxicity was assessed using the SkinEthic® Reconstructed Human Epidermis (RHE) model. Phototoxicity: photo-irritation was assessed using the 3T3NRU (Neutral Red Uptake) assay. Mutagenicity: bacterial reverse mutation Ames test was used. Genotoxicity: micronucleus test using cultured human lymphocytes. Skin sensitization potential was assessed using RHE test methods (cytokine IL-18 release measurement (SENS-IL18 assay) and genomic SENS-IS) and genomic GARD assays. Abbreviation: NA, not applicable. No adverse events were reported throughout the studies. SLT-001 was well tolerated with no clinical signs of intolerance and reports of discomfort at any of the studies. ​ Excipients and Bases: Numerous Topical Carriers are available in the realm of Pharmaceuticals, Topical Drug formulas are complex because of the need for a Vehicle Formula tailored specifically to the API, In our case SLT-001 or SLT-008. Each Carrier is usually a multitude of Excipients That are formulated alongside the active ingredient. Orientating our Carrier around the API(Active Pharmaceutical Ingredient) Requires us to know the solubility of the molecule, Lipophilicity, Molecular weight and polarity, and Place of Application, Each of these are crucial in verifying the Stability of the API. Luckily, This has been done for us so all we need to do is find the most optimized vehicle is look it up lulz​ API Solubility Lipophilicity Molecular Weight Polarity Place of Application SLT-001 Bad Solubility In Water due to it's lipid count (cLogP):5.2 MW ≈527 g/mol Low Polarity Epidermis, Melanocytes dnr Requires oil based vehicle highly lipoholic by nature to ease passage through skin layers associates with poor water solubility Requires higher strength penetrators due to size Mixed Excipients needed for proper stability Penetration Excipient Focused topical Now that we know the API Profile for SLT-001 and have over-viewed what specific Vehicle Types will work we can develop a Formula.​ ​ Clinical Trial Formulas A,B B Recommended:​ Usage and Importance:​ ☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲ ☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲ SLT-001 Formulated 2% with Exipients: 2% SLT-001: Spoiler: SLT-001 Sourcing: A very niche compound that seems all but proprietary to a company called SOLTEGO, Might be a good idea to check B2B sites like Echemi or madeinchina. If you don't find it, YKL-06-061 is the next best option, formulation for that will be incredibly similar if not exactly the same, SLT-001 seems to be either YKL-06-061 under another name or based off it. Early formulations of SLT-001 for ex vivo studies used the same pharmaceutical vehicle concentrations as YKL-06-061, moreover they are structurally similar with a identical Molecular weight and structure groups: YKL-06-061 is a cyclobutyl, xylyl, methylpiperazinylphenylamino pyrimidopyrimidinone SLT-001 is a Cyclobutyl Xylyl, Methylpiperizinylphenylamino Dihydropyrimidopyrimidinone Since they are so similar YKL-06-061 can likely become a alternative for this formula if SLT-001 isn't found Or you can beg the ngas at NUVIAN France SARL CRO to make SLT-001 for u idk lol (Formula A): 70% ethanol (Formula B): 65% Ethanol Spoiler: Ethanol Sourcing: 200 Proof Food Grade Ethanol 200 Proof Food Grade Ethanol Can be purchased easily on through vendors, Concentration is important in Formulation. 20% Water Spoiler: Water Sourcing: Purified Water should be Exclusively Used Just got to your local New Delhi Convenience store 7% Butylene Glycol Spoiler: Butylene Glycol Sourcing: Butylene Glycol, Penetration Enhancer and Solubilizer Easy to buy literally get off amazon, 1,3-Ratio Butylene Glycol Cosmetic Grade (250 mL / 8.45 Oz) 1% Sepimax Zen Spoiler: Sepimax Zen Sourcing: Used in creation of Aqueous Gel Topicals Sepimax Zen Raw Polymer Powder (FORMULA B) 5% Dimethyl Isossorbide(DMI) Spoiler: Dimethyl Isossorbide Sourcing: Low Irritant Penetration Enhancer Dimethyl Isosorbide (DMI) Ethyl Alcohol: Most Often used as a solvent for APIs due to it's exceptional ability to solute oil and water based substances, it's a rapid evaporator due to it's structural similarity to isopropyl alcohol, making it a great choice for cosmetic appliances.​ Water: Water is present in most Topical Formulations serving as a solvent for many APIs and as a penetration enhancer because of the skins natural absorption of water, usually paired with co solvents because of low water solubility sometimes found in APIs​ Butylene Glycol: Alcohol based Excipient is a Primary Solvent, Humectant, antibacterial agent, and an emolient, found in water based systems as a substitute for propylene glycol, and is chosen in formulations based on serums, creams, and hair product creation.​ Sepimax Zen: (proprietary product no cool chemical image) Sepimax Zen(Polyacrylate Crosspolymer-6) is a solution that enables the formulation to have enhanced thickening and stabilization, most carrier types(gels, creams, emulsions) are compatible with Sepimax Zen.​ (FORMULA B) Dimethyl Isossorbide: Dimethyl Isosorbide(DMI) is a co-solvent used to carry APIs more evenly across the skin, its incredibly tolerated low irritant solvent that is great for high Molecular weight APIs because of it's lightness and stabilization capabilities.​

(Formula A and B listing Differ for ingredients, simply based off the Clinical Trial, only difference is DMI is added and the water concentration is dropped to 15% in Formula B
Formula B might be preferred for enhanced Penetration)



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Formulation Instructions:​

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Equipment:​	Steps:​
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Milligram Scale 50g x 0.001g, Powder Scale 0.001g Accuracy Required for weighing out small quantities like 1% Sepimax Zen or 2% SLT-001 Link on Amazon​ White Color Stainless Steel Laboratory PTFE Stir Plate Bar (30 Mm/ 1.18 Inch), Magnetic Stirrer Stainless Steel Max Stirring Capacity: 3000ml Needed for first phase of Formulation, easy to use Beaker mixing toolset Link on Amazon /Link on Amazon Nitrile Chemical Resistant Medical Cooking Cleaning Disposable Gloves​ Protects the skin from coming in-contact with raw penetrative chemicals Link on Amazon EISCO Erlenmeyer Flask, 250ml - Borosilicate Glass - with PTFE Screw Cap​ Prevents ethanol evaporation and used to measure liquid amount Link on Amazon Digital Lab Scale 600g x 0.01g Precision Analytical Balance 0.01g Accuracy​ Needed for weighing bulk liquids(Ethanol DMI, Water, Total liquids) Link on Amazon 100mm Plain Watch Glass Beaker Cover/70mm Plain Watch Glass Beaker Cover, Karter Scientific 213H10-11​ Necessary during Sepimax Hydration Link on Amazon Karter Scientific, 3.3 Boro, Griffin Low Form, Glass Beaker Set - 6 Sizes - 10ml, 50ml, 100ml, 250ml, 500ml, 1000ml​ Necessary during Sepimax Hydration, Phase 2, And Final Mixing Link on Amazon 15PCS Stainless Steel Micro Scoop Set, 22cm Lab Sampling Spoon​ Needed for Accurate Powder dosages on scale Link on Amazon 6 Pieces Glass Pipettes 10ml 5ml 3ml 2ml 1ml 0.5ml Glass Graduated Dropper Pipette, Transfer for Liquid Essential Oil​ Needed for Transfer of smaller concentrated ingredients Link on Amazon Silicone Spatula - 8-Inch Slate - Heat-Resistant Up to 425°F - Non-Stick Seamless Food Grade Silicone​ Good for Scraping Beakers and manual mixing, Silicone needed Link on Amazon​ Method Of Dispensary:​ LuerLock Syringes: A cheap option if for some reason ur a brokie after buying this, either method will work for storage/dispensary but for long term i would recommend Airless pump bottles. Also needed for putting Formula in the Pump Bottles.​ Airless Pump Bottles: Great option for storage, Sepimex and gel based's dont work well with traditional pump bottles because of air bubbles destroying stability, id recommend for long term and it looks cool ​ ​	Visual Guides and References:​ Spoiler: Sepimax Zen Formulating: Directions Sprinkle Sepimax Zen over the aqueous phase and allow it to hydrate without stirring for several hours (up to 8), or disperse it by blending at low speed (~500 rpm), gradually increasing to ~1500 rpm as electrolytes are added, then let it hydrate for about 10 minutes. To create a cream gel, sprinkle Sepimax Zen into either the cold or hot oil phase, then add the oil phase to the water phase. Up to 25% oil can be incorporated when paired with a natural polymer such as xanthan gum, guar gum, or 1% gelatin. Warning For external use only. Avoid contact with eyes. Keep out of reach of children. Store tightly closed in a cool, dry place away from sunlight. Spoiler: References: (Just General Videos so you can get a grasp of the process) PHASE 1:​ Firstly, gather all of your materials and equipment together in one place After you have verified everything is there, begin by:​ Moving both your 100ML Erlenmeyer Flask and 500g-600g x 0.01 scale in front of you,​ Then, place the Erlenmeyer Flask on the Scale, and set the scale start weight to 0.00g​ Bring the 200 Proof Ethanol and get ready to pour into the flask siting on the Scale,​ Once your ready, unscrew the Erlenmeyer Flask Screw Top, watch the Scale screen and begin pouring, wait until the scale says 70.00g, stop pouring and set the Ethanol off to the side​ If you chose to do Formula B, Find you're 10mL glass pipette, then extract the Dimethyl Isossorbide and transfer into the Flask sitting on the scale, Do this until you have succesfully added 5.00g of DMI​ Locate your Milligram Scale 50g x 0.001g and put it infront of you, grab a small glass bowl or anything and put it on the scale, setting it as base-weight.​ Next Open your bag of SLT-001 Powder; using the Micro scoop set, drop Small Amounts of SLT-001 Powder into the glass bowl, accurately weigh 2.0g of SLT-001.​ Using the amount of powder you have now weighed to be equal to 2.0g, transfer it into the Erlenmeyer Flask​ After the SLT-001 API has come in contact with the solution in the Flask, Find the 30mm PTFE Magnetic stir bar listed, and drop it into the flask. immediately after, seal it with the provided PTFE Screw Top on the flask​ After the Erlenmeyer Flask has been sealed, Relocate it to the Magnetic Stir Plate Provided and place it on top​ Turn on the Magnetic Stir Plate at a medium speed(300-700 RPM) until the SLT-001 Solution is 90% transparent with little to none particles.​ Take the Erlenmeyer Flask Containing the solution off the Magnectic Stir Plate and leave it off to the side​ Phase 2:​ Place the 250mL Griffin Low Form Glass Beaker on the 500g-600g x 0.01 scale you have, set the scale start weight to 0.00g​ Find you're Purified water and pour (Formula A: 20g, Formula B: 15g) into the beaker and weigh until it reaches the listed weights, afterwards put the Purified Water bottle off to the side for later​ Now, grab the Butylene Glycol unscrew the cap, and using the 10mL glass pipette, transfer 7g into the 250mL Griffin Low Form Glass Beaker(beaker with water), watching the scale as you're doing it to make sure it's the correct amount​ When you have 7g of Butylene Glycol, using one of the Microscoops set pieces, stir gently for only a moment and set aside the mixture for now​ Using the Milligram Scale 50g x 0.001g, grab another glass bowl and place on the scale, repeating the same process of setting the base weight​ Next, Grab the bag of Sepimax Zen powder, using the micro Scoops dumping small amounts into the bowl and accurately weigh to 1g​ Grab the mixture of Butlyene Glycol and Water; place it in front of you.​ Take the weighed Sepimax Zen powder and SLOWLY sprinkle over the surface of the mixture​ Typically after this step you have to wait 8h for Sepimax Zen to Hydrate properly, but there is another method that works just aswell​ In the mixture, drop a Magnetic stir bar inside, and move it onto the Magnetic stirplate​ Begin sprinkling the Sepimax Zen Powder with medium speed(400-500 rpm)​ Once the powder seems to all have been wetted, increase mixing speed​ Mix until hydrated and free of particles.​ Cover the Mixture beaker opening with the Watch Glass Beaker Cover provided​ Let the Mixture sit for 20-25 minutes(Until it turns into a translucent gel so maybe more)​ NOTE: You may need to manually mix after the gel starts forming, the Magnetic stir bar can get stuck potentially)​ After the Sepimax Zen in the Mixture has Hydrated Correctly(translucent gel appearance),​ Stir GENTLY with a Silicone Spatula and remove the Stir bar if you used it.​ Let The Mixture sit for 5 minutes​ Phase 3:​ Begin by moving both the Erlenmeyer and Gel Mixture Flasks in front of you​ Place the Beaker containing the Gel Mixture on the magnetic stir plate, and insert a Magnetic stir-bar(again), Put the speed to low-medium (300-400 rpm this time around)​ Remove the PTFE Screw Top from the Erlenmeyer Flask and SLOWLY POUR in a very SMALL INCREMENT, into the Gel Mixture Flask while it is stirring​ If the Magnetic stir bar gets stuck again Switch to Manual Mixing until it is clear​ Final Phase:​ After you have combined both Mixtures and it is perfectly homogenous, cover the beaker with another Watch Glass Cover​ Find you're 60 mL Luer Lock Syringe and remove the plunger from it​ Grab you're Finished Gel and using the Silicone Spatula scrape into the back of the syringe​ After a decent amount has filled the syringe, put the Finished gel Flask to the side​ Grab the syringe plunger and slowly re-insert into the Syringe, once the plunger is mostly in, slowly push out excess air making sure not to accidently push out the Gel, Leave the Syringe to the side​ Find you're Airless Pump Bottle and using the syringe, Push the contents into the bottom of the Bottle​ Pay attention while doing this, having air bubles isn't optimal for the formulation​ After the Bottle is Filled put the pump head on​ YOU have just made a topical tanner!!!!! Extra Tidbit: Keep the Pump bottle out of the sun and at room temperature to keep the formula good ​

BE CAREFUL WITH ETHANOL IT'S FLAMMABLE UNLESS U WANNA BURN UR ASS TO DEATH
make sure ur doing this in a well ventilated space and try not to inhale fumes
KEEP UR FAMILY AWAY NEEGY
(For things like goggles and extra protection i feel it comes down to common sense instead of necessity. I often see full respiratory protection being recommended which just isn't required and is extra money)​

Conclusion and Extra:​

---

SIK Inhibitors are an interesting group of kinase inhibitors that have numerous purposes in pharmacotherapy, with albeit mild implications of influence, they still hold presidence in therapeutic application ranging from Osteoporosis therapy to Fat loss Medication. SIK-2 Inhibitors have shown great promise in changing skin pigmentation for extended periods of time, up to 4 weeks potentially more. Moreover, It's a Topical agent so it's ease of use might make it another choice for Tanning, other benefits that have been observed is it's ability to enhance DNA repair in keratinocytes and fibroblasts, and decrease expression of the MMP-1; a key marker for photoaging. Overall with no worrisome side effects brought to light regarding inhibition effects on neighboring pathways, SIK2 inhibitors are a great alternative to Melontan I/II, also one of the few ways soulless gingers can get a tan jfl.​

If the reception on this Guide does well i'll likely make another one on a different topic lmk if u guys would like that thread took genuinely a week to make ​

Tags:

Spoiler: tagging bums:

@Feuerwehr @Paul.jnxy @Regret @Scarlet @Stalker
@nwed @shedontluv-U @Anakin. @Daquavius Jr. 3rd @Lexapro @negative @nestivv @Scandi. @76.1 @alurmo @pleasevanity @buccalfatremoval @Askinov

​

 

[elxbp]

Oooh hymen hymen

 

[Stalker]

Hmm inb4 botb

my investment shall bring me lots of fortune

will read

 

[elxbp]

Hmm inb4 botb

my investment shall bring me lots of fortune will read

Yeah had to secure my spot

 

[bonesmasher245]

very nice very nice

 

[Shirobon]

Hmm inb4 botb

def not botb but i think its useful

my investment shall bring me lots of fortune

will read

yay

 

[j1gga]

dnr but seems high effort

 

[Shirobon]

dnr but seems high effort

Read but it took awhile ye

 

[Askinov]

@Gargantuan ts msy be botb

 

[Regret]

Inb4 BOTB

 

[Shirobon]

@Gargantuan ts msy be botb

watttt

 

[Shirobon]

Inb4 BOTB

glad yall like it

 

[Paul.jnxy]

Prerequisites to this guide:​

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MOBILE USERS PLEASE USE DESKTOP SITE OPTION IN SETTINGS OR ZOOM OUT It's fucking unreadable if you dont I have NOT tested the Formulations myself found later in the guide please use with discretion First Guide guys formatting and writing all over the place chill on me anyways enjoy reading ​

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Glossary:​

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Explanation of SIK

Melanogenesis Overview & Relation to SIK

SIK Inhibition

Trials & Findings

Topical Formulation

Salt-inducible kinases:​

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TL;DR:
SIK is a family of proteins found in our bodies that regulates lots of stuf including SIK2's regulation of tanning proccess luh bruh



Process of Melanogenesis:​

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TL;DR:
melanogenesis is process that make u tan
​

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Now that you understand the basic overview of Salt-inducible kinases(SIK) and the process of melanin production,
how does SIK2 factor into the regulation of Melanogenesis and what does SIK Inhibition overall mean for Pharmacotherapy?
View attachment 5399043
(nigga holding queef juice)​

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SIK Inhibition:​

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☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲

☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲

​ click me if hard to read lulz​ View attachment 5400777View attachment 5400776 View attachment 5400795View attachment 5400797​ click me if hard to read lulz​

To Start, SIK Inhibitors were originally developed to explore the biological functions of the SIK family without the need of Gene Manipulation, A notable Inhibitor like HG-9-91-01 was first deployed to inhibit all three isoforms of the family, with differentiating levels of inhibition, Many others were developed after with the same goal in mind. An interesting use case of a separate SIK inhibitor, specifically YKL-05-099(Derived from HG-9-91-09) in a study was shown to have an effect on osteocytes due to it's higher selectivity through PKA-dependent phosphorylation downregulation(PTH signaling cascade) although more specifically the reduction of HDAC4/5 phosphorlation in osteocytes, as a result downregulating the SOST protein expression in osteocytes, YKL-05-099 also inhibits the CSF1R Receptor for M-CSF inducing appositional growth without increasing osteocytes activity(Bone Resorption). A Similar selective Inhibitor(SK-124), SIK2/3 Inhibitor, was found to be far more Potent than YKL-05-099 in Osteogenesis with the addition of net zero short term toxicity recorded. It works in an analogous approach to YKL-05-099, both suppressing phosphorylation of HDAC4/5 but also CRTC2. For both YKL-05-099 and SK-124 were shown improved bone formation and mass, mimicking PTH1R Signaling of Osteogenesis, although most trials were done in vivo of animals some were done on humans and showed no difference in effects.​ ​ SIK1 and SIK2 both have Important Roles in the Regulation of lipogenesis. SIK1 acts through the inhibition of the sterol regulatory element-binding protein(SREBP-1c), which is a main factor in fatty-acid and triglyceride synthesis, Inhibiting this protein Surpresses the expression of Fatty acid and Acetyl-CoA carboxylase synthesis, using an Inhibitor for this purpose will likely slow the process of fat creation, furthermore SIK Inhibition has potential implications for future Metabolic therapies for fat loss beyond the Current GLP-1 Based agonists I.e (Retatrutide, Semaglutide, Tirzepatide).​ SIK2 Inhibition: In almost all cases of SIK Inhibition cAMP/PKA are present, SIK2 Inhibition in regards to pharmaceutical targeting of Melanin Synthesis is no different, earlier in the thread i mentioned the MC1R regulator and the other important pathways in Melanogenesis, SIK2's role in this system is by directly controlling the activity of cAMP-regulated transcriptional coactivators(CTRCs) and CREB (cAMP response element-binding protein), a key transcription factor. The promotion of these responses enhances the MITF expression sequentially upregulating melanin synthesis(Melanogenesis), In other words, usage of a SIK2 Inhibitor can make you more tan. In former studies Topical SIK2 Inhibitors were unlikely to work effectively as the Outer Skin Barrier in humans are far harder to penetrate than the animal skin used in vivo studies, however one named YKL-06-061 showed more promise than others, eventually recent advancements led to 2nd Generation SIK2 Inhibitors being developed which had far better Penetration Capabilities. Those being: SLT-008 and SLT-001, Moreover usage of said Inhibitors after UV-Based DNA Damage led to promoted tissue repair and collagen protection. The suppression of the MMP-1 enzyme which is a main factor in aging caused by UV Damage, was identified to be present in Both Inhibitors aswell.​ Key:​ Term: Definition: Phosphorylation: phosphorylation noun​ The process of transferring a phosphate group from a donor to an acceptor; often catalysed by enzymes. Parathyroid hormone (PTH): key regulator of bone remodeling, the continuous process of bone resorption and formation. PTH indirectly stimulates osteoclast activity, promoting the release of calcium from the bone matrix to restore serum calcium levels. Appositional Growth: Appositional growth​ Definition noun Growth by forming new layers on the surface of pre-existing layers; process of increasing in thickness rather than length. Supplement In bones, this method of growth is accomplished by the addition of newly formed cartilage on the surface of the previously formed cartilage. The result is growth in diameter rather than in length. ​

Trials & Findings:​

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Study 1(IN VIVO HUMAN):​	Study 2(IN VIVO MICE, EX VIVO HUMAN SKIN):​
☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲	☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲
A series of SIK inhibitors featuring a pyrimidine-pyridone pharmacophore have been developed. The incorporated substituents allow for modulation of lipophilicity and physical properties, which, in turn, influence skin penetration. SLT-008 (Figure 1a) is a novel SIK inhibitor with high lipophilicity (clogP 6.66; Property Calculator, Molinspirations, Slovak Republic) and a molecular weight of 577.78. Similarly, SLT-001 (Figure 1B) has a clogP value of 5.2 and a molecular weight of 527.67 View attachment 5400994The biochemical potencies of SLT-008 and SLT-001 against the three SIK isoforms 1, 2 and 3 were determined with KinaseProfiler™ assays. SLT-008 and SLT-001 exhibited high potency against SIK1/2 and selectivity over SIK3, with IC50 of SIK1/2/3 being 5/8/>20 nM for SLT-008 and 7/14/>20 nM for SLT-001. To confirm their SIK cellular target engagement, a NanoBRET assay was performed. In this assay, engagement with a fluorescent tracer molecule that binds the ATP-binding site of SIK1 in a NanoLuc-SIK1 fusion leads to a BRET signal. A SIK1-binding ligand displaces the tracer, leading to a diminished signal. SLT-008 and SLT-001 bind to SIK1 strongly with an IC50 of 9.7 and 1.9 nM, respectively. SLT-008, SLT-001 or vehicle (ethanol 70%, propylene glycol 30%) were topically administered to an explant derived from a 67-year-old Caucasian woman (skin phototype II). The application was administered twice, a day before and after UV-B exposure. DNA damage was then assessed 24 h after irradiation. At 24 h post-UV-B exposure, CPD levels were significantly decreased by treatment with SLT-008 (60.1%, Figure 2b,c). Treatment with SLT-001 resulted in an even greater reduction in CPD levels, reaching 93.9%, These findings indicate that SIK inhibitors, such as SLT-001 and SLT-008, effectively reduce UV-induced DNA and tissue damage. View attachment 5400991Exposure of skin to UV radiation induces upregulation of MMP-1 expression, which leads to the breakdown of collagen, contributing to premature skin ageing (photoageing) [25, 26]. The protective effects of SIK inhibition were further evaluated by measuring MMP-1 levels. Skin explants were treated as outlined in Figure 2a. Following UV-B exposure, MMP-1 levels significantly increased by 139% compared to baseline (Figure 3a,b). Treatment with SLT-008 reduced MMP-1 levels by 52%, while SLT-001 achieved a greater reduction of 78% (Figure 3a,b). No significant reduction was observed with SLT-043 (Figure 3c,d), or with the photolyase treated group. MMP-1 expression was examined immediately after UV-R and 24 h post UV-R. As expected, immediately post UV-R MMP-1 was not induced at the View attachment 5401001protein level (Figure 5a,b). However, 24 h post-UV-R exposure, a significant induction of MMP1 was observed in the vehicle group in both the epidermis and dermis (Figure 5a indicated by black arrows), with an increase of 77%. In contrast, in the SLT-001 treated group, there was no significant increase In summary, we provide evidence that SIK inhibitors, SLT-001 and SLT-008, offer protection against UV-induced photodamage. Topical application of these cosmetic ingredients represents a powerful approach to mitigate UV-induced damage and photoageing, while potentially delivering broader cosmetic benefits.​ Inbal Rachmin, Le Varlet, B., Regazzetti, C., Thierry Passeron, Wang, J., Fisher, D. E., Philippe Schaison, & Braham Shroot. (2025). A novel approach to target skin photodamage: Topical application of salt inducible kinase inhibitors. International Journal of Cosmetic Science, 48(1), 1–15. https://doi.org/10.1111/ics.70003​	Topical Treatment with HG9-91-01 Causes Robust Darkening that Is Progressive and Reversible in Mc1re/e;K14-SCF MiceView attachment 5400939 (A–D) Shown here: (A) Mc1re/e;K14-SCF mice and Tyrc/c;K14-SCF mice before treatment (day 0) and after 7 days of treatment (day 7) with 30 μL vehicle control (70% ethanol, 30% propylene glycol) or 37.5 mM HG 9-91-01 (image is representative of n = 4 experiments). (B) Reflective colorimetry measurements (L∗ white-black color axis; n = 4, mean ± SEM) and (D) melanin extraction (image is representative of n = 4 experiments) of the Mc1re/e;K14-SCF mice and Tyrc/c;K14-SCF mice described in (A). (C) Skin sections of Mc1re/e;K14-SCF mice described in (A) stained with Fontana-Masson (eumelanin) (top two panels) or H&E (bottom two panels); (magnification, 400×). White arrows represent nuclear capping; scale bar represents 25 μm. (E) Mc1re/e;K14-SCF mice and Tyrc/c;K14-SCF mice before treatment (day 0) and after 6 days of treatment with 30 μL vehicle control (70% ethanol, 30% propylene glycol) or 37.5 mM HG 9-91-01 (day 6), and 40 days post-treatment (day 46) (vehicle mouse in day-46 photo is different from that in the day-0 and day-6 photos). (F and G) Reflective colorimetry measurements (CIE L∗ white-black color axis) of (F) Mc1re/e;K14-SCF mice and (G) Tyrc/c;K14-SCF mice treated as described in (E). Vehicle-treated Mc1re/e;K14-SCF mice: n = 5 (days 0–19), and n = 4 (days 24–34); HG 9-91-01-treated Mc1re/e;K14-SCF mice: n = 3; vehicle-treated Tyrc/c;K14-SCF mice: n = 3 (days 0–10), and n = 2 (days 11–20); HG 9-91-01-treated Tyrc/c;K14-SCF mice: n = 3 (mean ± SEM). For the graph in (B), statistical significance is reported as follows: ∗∗∗∗p < 0.0001, multiple t test analysis with the two-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli. For the graphs in (F) and (G), statistical significance is reported as follows: ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001, two-way ANOVA with Sidak’s multiple comparisons test comparing treatment to vehicle control at each time point. Treatment of human skin explants with passive topical application of the second-generation SIK inhibitors, YKL 06-061 and YKL 06-062, View attachment 5400958induced significant pigmentation after 8 days of treatment (1×/day), but no significant gross pigmentation was observed in skin treated with HG 9-91-01 (Figure 4A). Fontana-Masson staining revealed increased melanin content in skin treated with YKL 06-061 or YKL 06-062 and marginally increased melanin in skin treated with HG 9-91-01, as compared with control. This effect was reproducible with independent preparations of synthesized drugs applied passively (via pipette) to the top of different human skin explants. Mechanical application of the first-generation SIK inhibitor HG 9-91-01, by rubbing via an applicator, induced significant gross pigmentation , and increased melanin content was observed upon Fontana-Masson staining of skin sections, suggesting that HG 9-91-01’s limited human skin penetration can be, at least partially, overcome through mechanical application. YKL 06-061 and YKL 06-062 did not require mechanical application (rubbing) to induce significant human epidermal darkening. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk.​ Mujahid, Nisma. “(PDF) a UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin.” Research Gate, 13 June 2017, www.researchgate.net/publication/317576045_A_UV-Independent_Topical_Small-Molecule_Approach_for_Melanin_Production_in_Human_Skin.​

​

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Topical Formulation:
​

Spoiler: DISCLAMER PLEASE READ: ANOTHER DISCLAIMER I AM IN NO WAY AN EXPERT ON PHARAMCUETICAL VEHICLES/TOPICAL AGENT DEVELOPMENT, IF YOU PLAN TO DIY PLEASE USE DISCRETION

From all that was gathered from this Guide along with the Studies, the choice for a Topical agent goes down to SLT-001 and SLT-008, both with similar benefits although they differ in Lipophilicity and Molecular weight, which are thing to consider when Formulation is undergoing. SLT-001 was found to be more compatible and had a slightly higher reduction of UV Based Skin Damage, and was optimized solely for Clinical Trials(Human Testing). In my opinion this would be the main choice as it is the most promising and seemingly compatible Topical SIK Inhibitor currently available.​

SLT-001 and SLT-008 Skin Safety Profile:​ Toxicological endpoint OECD TG SLT-001 SLT-008 Skin irritation HRE 439 Non skin irritant Non skin irritant Phototoxicity 3 T3 NRU 498 Non phototoxic Non phototoxic Mutagenicity (Ames) 471 Non mutagenic Non mutagenic Genotoxicity (Micronucleus) 487 Non aneugen and non clastogen Non aneugen and non clastogen Skin sensitization SENS-IL18 NA / Non sensitizer Skin sensitization SENS-IS NA Non sensitizer Non sensitizer Skin sensitization GARD 442E Sensitizer NA

Note: Skin irritation: cytotoxicity was assessed using the SkinEthic® Reconstructed Human Epidermis (RHE) model. Phototoxicity: photo-irritation was assessed using the 3T3NRU (Neutral Red Uptake) assay. Mutagenicity: bacterial reverse mutation Ames test was used. Genotoxicity: micronucleus test using cultured human lymphocytes. Skin sensitization potential was assessed using RHE test methods (cytokine IL-18 release measurement (SENS-IL18 assay) and genomic SENS-IS) and genomic GARD assays. Abbreviation: NA, not applicable. No adverse events were reported throughout the studies. SLT-001 was well tolerated with no clinical signs of intolerance and reports of discomfort at any of the studies. ​ Excipients and Bases: Numerous Topical Carriers are available in the realm of Pharmaceuticals, Topical Drug formulas are complex because of the need for a Vehicle Formula tailored specifically to the API, In our case SLT-001 or SLT-008. Each Carrier is usually a multitude of Excipients That are formulated alongside the active ingredient. Orientating our Carrier around the API(Active Pharmaceutical Ingredient) Requires us to know the solubility of the molecule, Lipophilicity, Molecular weight and polarity, and Place of Application, Each of these are crucial in verifying the Stability of the API. Luckily, This has been done for us so all we need to do is find the most optimized vehicle is look it up lulz​ API Solubility Lipophilicity Molecular Weight Polarity Place of Application SLT-001 Bad Solubility In Water due to it's lipid count (cLogP):5.2 MW ≈527 g/mol Low Polarity Epidermis, Melanocytes dnr Requires oil based vehicle highly lipoholic by nature to ease passage through skin layers associates with poor water solubility Requires higher strength penetrators due to size Mixed Excipients needed for proper stability Penetration Excipient Focused topical Now that we know the API Profile for SLT-001 and have over-viewed what specific Vehicle Types will work we can develop a Formula.​ ​ Clinical Trial Formulas A,B B Recommended:​ Usage and Importance:​ ☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲ ☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲ SLT-001 Formulated 2% with Exipients: 2% SLT-001: Spoiler: SLT-001 Sourcing: A very niche compound that seems all but proprietary to a company called SOLTEGO, Might be a good idea to check B2B sites like Echemi or madeinchina. If you don't find it, YKL-06-061 is the next best option, formulation for that will be incredibly similar if not exactly the same, SLT-001 seems to be either YKL-06-061 under another name or based off it. Early formulations of SLT-001 for ex vivo studies used the same pharmaceutical vehicle concentrations as YKL-06-061, moreover they are structurally similar with a identical Molecular weight and structure groups: YKL-06-061 is a cyclobutyl, xylyl, methylpiperazinylphenylamino pyrimidopyrimidinone SLT-001 is a Cyclobutyl Xylyl, Methylpiperizinylphenylamino Dihydropyrimidopyrimidinone Since they are so similar YKL-06-061 can likely become a alternative for this formula if SLT-001 isn't found Or you can beg the ngas at NUVIAN France SARL CRO to make SLT-001 for u idk lol (Formula A): 70% ethanol (Formula B): 65% Ethanol Spoiler: Ethanol Sourcing: 200 Proof Food Grade Ethanol 200 Proof Food Grade Ethanol Can be purchased easily on through vendors, Concentration is important in Formulation. 20% Water Spoiler: Water Sourcing: Purified Water should be Exclusively Used Just got to your local New Delhi Convenience store View attachment 5413502 7% Butylene Glycol Spoiler: Butylene Glycol Sourcing: Butylene Glycol, Penetration Enhancer and Solubilizer Easy to buy literally get off amazon, 1,3-Ratio Butylene Glycol Cosmetic Grade (250 mL / 8.45 Oz) 1% Sepimax Zen Spoiler: Sepimax Zen Sourcing: Used in creation of Aqueous Gel Topicals Sepimax Zen Raw Polymer Powder (FORMULA B) 5% Dimethyl Isossorbide(DMI) Spoiler: Dimethyl Isossorbide Sourcing: Low Irritant Penetration Enhancer Dimethyl Isosorbide (DMI) Ethyl Alcohol: Most Often used as a solvent for APIs due to it's exceptional ability to solute oil and water based substances, it's a rapid evaporator due to it's structural similarity to isopropyl alcohol, making it a great choice for cosmetic appliances.​ Water: Water is present in most Topical Formulations serving as a solvent for many APIs and as a penetration enhancer because of the skins natural absorption of water, usually paired with co solvents because of low water solubility sometimes found in APIs​ Butylene Glycol: Alcohol based Excipient is a Primary Solvent, Humectant, antibacterial agent, and an emolient, found in water based systems as a substitute for propylene glycol, and is chosen in formulations based on serums, creams, and hair product creation.​ Sepimax Zen: View attachment 5412763 (proprietary product no cool chemical image) Sepimax Zen(Polyacrylate Crosspolymer-6) is a solution that enables the formulation to have enhanced thickening and stabilization, most carrier types(gels, creams, emulsions) are compatible with Sepimax Zen.​ (FORMULA B) Dimethyl Isossorbide: View attachment 5412973 Dimethyl Isosorbide(DMI) is a co-solvent used to carry APIs more evenly across the skin, its incredibly tolerated low irritant solvent that is great for high Molecular weight APIs because of it's lightness and stabilization capabilities.​

(Formula A and B listing Differ for ingredients, simply based off the Clinical Trial, only difference is DMI is added and the water concentration is dropped to 15% in Formula B
Formula B might be preferred for enhanced Penetration)



​

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Formulation Instructions:​

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Conclusion and Extra:​

---

SIK Inhibitors are an interesting group of kinase inhibitors that have numerous purposes in pharmacotherapy, with albeit mild implications of influence, they still hold presidence in therapeutic application ranging from Osteoporosis therapy to Fat loss Medication. SIK-2 Inhibitors have shown great promise in changing skin pigmentation for extended periods of time, up to 4 weeks potentially more. Moreover, It's a Topical agent so it's ease of use might make it another choice for Tanning, other benefits that have been observed is it's ability to enhance DNA repair in keratinocytes and fibroblasts, and decrease expression of the MMP-1; a key marker for photoaging. Overall with no worrisome side effects brought to light regarding inhibition effects on neighboring pathways, SIK2 inhibitors are a great alternative to Melontan I/II, also one of the few ways soulless gingers can get a tan jfl.​

If the reception on this Guide does well i'll likely make another one on a different topic lmk if u guys would like that thread took genuinely a week to make ​

Tags:

Spoiler: tagging bums:

@Feuerwehr @Paul.jnxy @Regret @Scarlet @Stalker
@nwed @shedontluv-U @Anakin. @Daquavius Jr. 3rd @Lexapro @negative @nestivv @Scandi. @76.1 @alurmo @pleasevanity @buccalfatremoval @Askinov

View attachment 5398700View attachment 5399053
​

Holy shit. As a mayocel I really needed this lol. Tysm, BOTB worthy read every molecule

 

[Shirobon]

Holy shit. As a mayocel I really needed this lol. Tysm, BOTB worthy read every molecule

thx brocel
be very careful with the vapors when formulating but other than that its pretty safe yo

 

[Scarlet]

Prerequisites to this guide:​

---

MOBILE USERS PLEASE USE DESKTOP SITE OPTION IN SETTINGS OR ZOOM OUT It's fucking unreadable if you dont I have NOT tested the Formulations myself found later in the guide please use with discretion First Guide guys formatting and writing all over the place chill on me anyways enjoy reading ​

Please Use Darkmode:
Click Here

Spoiler: Thread Songs:

Glossary:​

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Explanation of SIK

Melanogenesis Overview & Relation to SIK

SIK Inhibition

Trials & Findings

Topical Formulation

Salt-inducible kinases:​

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TL;DR:
SIK is a family of proteins found in our bodies that regulates lots of stuf including SIK2's regulation of tanning proccess luh bruh



Process of Melanogenesis:​

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TL;DR:
melanogenesis is process that make u tan
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Now that you understand the basic overview of Salt-inducible kinases(SIK) and the process of melanin production,
how does SIK2 factor into the regulation of Melanogenesis and what does SIK Inhibition overall mean for Pharmacotherapy?
View attachment 5399043
(nigga holding queef juice)​

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SIK Inhibition:​

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☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲

☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲

​ click me if hard to read lulz​ View attachment 5400777View attachment 5400776 View attachment 5400795View attachment 5400797​ click me if hard to read lulz​

To Start, SIK Inhibitors were originally developed to explore the biological functions of the SIK family without the need of Gene Manipulation, A notable Inhibitor like HG-9-91-01 was first deployed to inhibit all three isoforms of the family, with differentiating levels of inhibition, Many others were developed after with the same goal in mind. An interesting use case of a separate SIK inhibitor, specifically YKL-05-099(Derived from HG-9-91-09) in a study was shown to have an effect on osteocytes due to it's higher selectivity through PKA-dependent phosphorylation downregulation(PTH signaling cascade) although more specifically the reduction of HDAC4/5 phosphorlation in osteocytes, as a result downregulating the SOST protein expression in osteocytes, YKL-05-099 also inhibits the CSF1R Receptor for M-CSF inducing appositional growth without increasing osteocytes activity(Bone Resorption). A Similar selective Inhibitor(SK-124), SIK2/3 Inhibitor, was found to be far more Potent than YKL-05-099 in Osteogenesis with the addition of net zero short term toxicity recorded. It works in an analogous approach to YKL-05-099, both suppressing phosphorylation of HDAC4/5 but also CRTC2. For both YKL-05-099 and SK-124 were shown improved bone formation and mass, mimicking PTH1R Signaling of Osteogenesis, although most trials were done in vivo of animals some were done on humans and showed no difference in effects.​ ​ SIK1 and SIK2 both have Important Roles in the Regulation of lipogenesis. SIK1 acts through the inhibition of the sterol regulatory element-binding protein(SREBP-1c), which is a main factor in fatty-acid and triglyceride synthesis, Inhibiting this protein Surpresses the expression of Fatty acid and Acetyl-CoA carboxylase synthesis, using an Inhibitor for this purpose will likely slow the process of fat creation, furthermore SIK Inhibition has potential implications for future Metabolic therapies for fat loss beyond the Current GLP-1 Based agonists I.e (Retatrutide, Semaglutide, Tirzepatide).​ SIK2 Inhibition: In almost all cases of SIK Inhibition cAMP/PKA are present, SIK2 Inhibition in regards to pharmaceutical targeting of Melanin Synthesis is no different, earlier in the thread i mentioned the MC1R regulator and the other important pathways in Melanogenesis, SIK2's role in this system is by directly controlling the activity of cAMP-regulated transcriptional coactivators(CTRCs) and CREB (cAMP response element-binding protein), a key transcription factor. The promotion of these responses enhances the MITF expression sequentially upregulating melanin synthesis(Melanogenesis), In other words, usage of a SIK2 Inhibitor can make you more tan. In former studies Topical SIK2 Inhibitors were unlikely to work effectively as the Outer Skin Barrier in humans are far harder to penetrate than the animal skin used in vivo studies, however one named YKL-06-061 showed more promise than others, eventually recent advancements led to 2nd Generation SIK2 Inhibitors being developed which had far better Penetration Capabilities. Those being: SLT-008 and SLT-001, Moreover usage of said Inhibitors after UV-Based DNA Damage led to promoted tissue repair and collagen protection. The suppression of the MMP-1 enzyme which is a main factor in aging caused by UV Damage, was identified to be present in Both Inhibitors aswell.​ Key:​ Term: Definition: Phosphorylation: phosphorylation noun​ The process of transferring a phosphate group from a donor to an acceptor; often catalysed by enzymes. Parathyroid hormone (PTH): key regulator of bone remodeling, the continuous process of bone resorption and formation. PTH indirectly stimulates osteoclast activity, promoting the release of calcium from the bone matrix to restore serum calcium levels. Appositional Growth: Appositional growth​ Definition noun Growth by forming new layers on the surface of pre-existing layers; process of increasing in thickness rather than length. Supplement In bones, this method of growth is accomplished by the addition of newly formed cartilage on the surface of the previously formed cartilage. The result is growth in diameter rather than in length. ​

Trials & Findings:​

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Study 1(IN VIVO HUMAN):​	Study 2(IN VIVO MICE, EX VIVO HUMAN SKIN):​
☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲	☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲
A series of SIK inhibitors featuring a pyrimidine-pyridone pharmacophore have been developed. The incorporated substituents allow for modulation of lipophilicity and physical properties, which, in turn, influence skin penetration. SLT-008 (Figure 1a) is a novel SIK inhibitor with high lipophilicity (clogP 6.66; Property Calculator, Molinspirations, Slovak Republic) and a molecular weight of 577.78. Similarly, SLT-001 (Figure 1B) has a clogP value of 5.2 and a molecular weight of 527.67 View attachment 5400994The biochemical potencies of SLT-008 and SLT-001 against the three SIK isoforms 1, 2 and 3 were determined with KinaseProfiler™ assays. SLT-008 and SLT-001 exhibited high potency against SIK1/2 and selectivity over SIK3, with IC50 of SIK1/2/3 being 5/8/>20 nM for SLT-008 and 7/14/>20 nM for SLT-001. To confirm their SIK cellular target engagement, a NanoBRET assay was performed. In this assay, engagement with a fluorescent tracer molecule that binds the ATP-binding site of SIK1 in a NanoLuc-SIK1 fusion leads to a BRET signal. A SIK1-binding ligand displaces the tracer, leading to a diminished signal. SLT-008 and SLT-001 bind to SIK1 strongly with an IC50 of 9.7 and 1.9 nM, respectively. SLT-008, SLT-001 or vehicle (ethanol 70%, propylene glycol 30%) were topically administered to an explant derived from a 67-year-old Caucasian woman (skin phototype II). The application was administered twice, a day before and after UV-B exposure. DNA damage was then assessed 24 h after irradiation. At 24 h post-UV-B exposure, CPD levels were significantly decreased by treatment with SLT-008 (60.1%, Figure 2b,c). Treatment with SLT-001 resulted in an even greater reduction in CPD levels, reaching 93.9%, These findings indicate that SIK inhibitors, such as SLT-001 and SLT-008, effectively reduce UV-induced DNA and tissue damage. View attachment 5400991Exposure of skin to UV radiation induces upregulation of MMP-1 expression, which leads to the breakdown of collagen, contributing to premature skin ageing (photoageing) [25, 26]. The protective effects of SIK inhibition were further evaluated by measuring MMP-1 levels. Skin explants were treated as outlined in Figure 2a. Following UV-B exposure, MMP-1 levels significantly increased by 139% compared to baseline (Figure 3a,b). Treatment with SLT-008 reduced MMP-1 levels by 52%, while SLT-001 achieved a greater reduction of 78% (Figure 3a,b). No significant reduction was observed with SLT-043 (Figure 3c,d), or with the photolyase treated group. MMP-1 expression was examined immediately after UV-R and 24 h post UV-R. As expected, immediately post UV-R MMP-1 was not induced at the View attachment 5401001protein level (Figure 5a,b). However, 24 h post-UV-R exposure, a significant induction of MMP1 was observed in the vehicle group in both the epidermis and dermis (Figure 5a indicated by black arrows), with an increase of 77%. In contrast, in the SLT-001 treated group, there was no significant increase In summary, we provide evidence that SIK inhibitors, SLT-001 and SLT-008, offer protection against UV-induced photodamage. Topical application of these cosmetic ingredients represents a powerful approach to mitigate UV-induced damage and photoageing, while potentially delivering broader cosmetic benefits.​ Inbal Rachmin, Le Varlet, B., Regazzetti, C., Thierry Passeron, Wang, J., Fisher, D. E., Philippe Schaison, & Braham Shroot. (2025). A novel approach to target skin photodamage: Topical application of salt inducible kinase inhibitors. International Journal of Cosmetic Science, 48(1), 1–15. https://doi.org/10.1111/ics.70003​	Topical Treatment with HG9-91-01 Causes Robust Darkening that Is Progressive and Reversible in Mc1re/e;K14-SCF MiceView attachment 5400939 (A–D) Shown here: (A) Mc1re/e;K14-SCF mice and Tyrc/c;K14-SCF mice before treatment (day 0) and after 7 days of treatment (day 7) with 30 μL vehicle control (70% ethanol, 30% propylene glycol) or 37.5 mM HG 9-91-01 (image is representative of n = 4 experiments). (B) Reflective colorimetry measurements (L∗ white-black color axis; n = 4, mean ± SEM) and (D) melanin extraction (image is representative of n = 4 experiments) of the Mc1re/e;K14-SCF mice and Tyrc/c;K14-SCF mice described in (A). (C) Skin sections of Mc1re/e;K14-SCF mice described in (A) stained with Fontana-Masson (eumelanin) (top two panels) or H&E (bottom two panels); (magnification, 400×). White arrows represent nuclear capping; scale bar represents 25 μm. (E) Mc1re/e;K14-SCF mice and Tyrc/c;K14-SCF mice before treatment (day 0) and after 6 days of treatment with 30 μL vehicle control (70% ethanol, 30% propylene glycol) or 37.5 mM HG 9-91-01 (day 6), and 40 days post-treatment (day 46) (vehicle mouse in day-46 photo is different from that in the day-0 and day-6 photos). (F and G) Reflective colorimetry measurements (CIE L∗ white-black color axis) of (F) Mc1re/e;K14-SCF mice and (G) Tyrc/c;K14-SCF mice treated as described in (E). Vehicle-treated Mc1re/e;K14-SCF mice: n = 5 (days 0–19), and n = 4 (days 24–34); HG 9-91-01-treated Mc1re/e;K14-SCF mice: n = 3; vehicle-treated Tyrc/c;K14-SCF mice: n = 3 (days 0–10), and n = 2 (days 11–20); HG 9-91-01-treated Tyrc/c;K14-SCF mice: n = 3 (mean ± SEM). For the graph in (B), statistical significance is reported as follows: ∗∗∗∗p < 0.0001, multiple t test analysis with the two-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli. For the graphs in (F) and (G), statistical significance is reported as follows: ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; ∗∗∗∗p < 0.0001, two-way ANOVA with Sidak’s multiple comparisons test comparing treatment to vehicle control at each time point. Treatment of human skin explants with passive topical application of the second-generation SIK inhibitors, YKL 06-061 and YKL 06-062, View attachment 5400958induced significant pigmentation after 8 days of treatment (1×/day), but no significant gross pigmentation was observed in skin treated with HG 9-91-01 (Figure 4A). Fontana-Masson staining revealed increased melanin content in skin treated with YKL 06-061 or YKL 06-062 and marginally increased melanin in skin treated with HG 9-91-01, as compared with control. This effect was reproducible with independent preparations of synthesized drugs applied passively (via pipette) to the top of different human skin explants. Mechanical application of the first-generation SIK inhibitor HG 9-91-01, by rubbing via an applicator, induced significant gross pigmentation , and increased melanin content was observed upon Fontana-Masson staining of skin sections, suggesting that HG 9-91-01’s limited human skin penetration can be, at least partially, overcome through mechanical application. YKL 06-061 and YKL 06-062 did not require mechanical application (rubbing) to induce significant human epidermal darkening. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk.​ Mujahid, Nisma. “(PDF) a UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin.” Research Gate, 13 June 2017, www.researchgate.net/publication/317576045_A_UV-Independent_Topical_Small-Molecule_Approach_for_Melanin_Production_in_Human_Skin.​

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Topical Formulation:
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Spoiler: DISCLAMER PLEASE READ: ANOTHER DISCLAIMER I AM IN NO WAY AN EXPERT ON PHARAMCUETICAL VEHICLES/TOPICAL AGENT DEVELOPMENT, IF YOU PLAN TO DIY PLEASE USE DISCRETION

From all that was gathered from this Guide along with the Studies, the choice for a Topical agent goes down to SLT-001 and SLT-008, both with similar benefits although they differ in Lipophilicity and Molecular weight, which are thing to consider when Formulation is undergoing. SLT-001 was found to be more compatible and had a slightly higher reduction of UV Based Skin Damage, and was optimized solely for Clinical Trials(Human Testing). In my opinion this would be the main choice as it is the most promising and seemingly compatible Topical SIK Inhibitor currently available.​

SLT-001 and SLT-008 Skin Safety Profile:​ Toxicological endpoint OECD TG SLT-001 SLT-008 Skin irritation HRE 439 Non skin irritant Non skin irritant Phototoxicity 3 T3 NRU 498 Non phototoxic Non phototoxic Mutagenicity (Ames) 471 Non mutagenic Non mutagenic Genotoxicity (Micronucleus) 487 Non aneugen and non clastogen Non aneugen and non clastogen Skin sensitization SENS-IL18 NA / Non sensitizer Skin sensitization SENS-IS NA Non sensitizer Non sensitizer Skin sensitization GARD 442E Sensitizer NA

Note: Skin irritation: cytotoxicity was assessed using the SkinEthic® Reconstructed Human Epidermis (RHE) model. Phototoxicity: photo-irritation was assessed using the 3T3NRU (Neutral Red Uptake) assay. Mutagenicity: bacterial reverse mutation Ames test was used. Genotoxicity: micronucleus test using cultured human lymphocytes. Skin sensitization potential was assessed using RHE test methods (cytokine IL-18 release measurement (SENS-IL18 assay) and genomic SENS-IS) and genomic GARD assays. Abbreviation: NA, not applicable. No adverse events were reported throughout the studies. SLT-001 was well tolerated with no clinical signs of intolerance and reports of discomfort at any of the studies. ​ Excipients and Bases: Numerous Topical Carriers are available in the realm of Pharmaceuticals, Topical Drug formulas are complex because of the need for a Vehicle Formula tailored specifically to the API, In our case SLT-001 or SLT-008. Each Carrier is usually a multitude of Excipients That are formulated alongside the active ingredient. Orientating our Carrier around the API(Active Pharmaceutical Ingredient) Requires us to know the solubility of the molecule, Lipophilicity, Molecular weight and polarity, and Place of Application, Each of these are crucial in verifying the Stability of the API. Luckily, This has been done for us so all we need to do is find the most optimized vehicle is look it up lulz​ API Solubility Lipophilicity Molecular Weight Polarity Place of Application SLT-001 Bad Solubility In Water due to it's lipid count (cLogP):5.2 MW ≈527 g/mol Low Polarity Epidermis, Melanocytes dnr Requires oil based vehicle highly lipoholic by nature to ease passage through skin layers associates with poor water solubility Requires higher strength penetrators due to size Mixed Excipients needed for proper stability Penetration Excipient Focused topical Now that we know the API Profile for SLT-001 and have over-viewed what specific Vehicle Types will work we can develop a Formula.​ ​ Clinical Trial Formulas A,B B Recommended:​ Usage and Importance:​ ☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲ ☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲☲ SLT-001 Formulated 2% with Exipients: 2% SLT-001: Spoiler: SLT-001 Sourcing: A very niche compound that seems all but proprietary to a company called SOLTEGO, Might be a good idea to check B2B sites like Echemi or madeinchina. If you don't find it, YKL-06-061 is the next best option, formulation for that will be incredibly similar if not exactly the same, SLT-001 seems to be either YKL-06-061 under another name or based off it. Early formulations of SLT-001 for ex vivo studies used the same pharmaceutical vehicle concentrations as YKL-06-061, moreover they are structurally similar with a identical Molecular weight and structure groups: YKL-06-061 is a cyclobutyl, xylyl, methylpiperazinylphenylamino pyrimidopyrimidinone SLT-001 is a Cyclobutyl Xylyl, Methylpiperizinylphenylamino Dihydropyrimidopyrimidinone Since they are so similar YKL-06-061 can likely become a alternative for this formula if SLT-001 isn't found Or you can beg the ngas at NUVIAN France SARL CRO to make SLT-001 for u idk lol (Formula A): 70% ethanol (Formula B): 65% Ethanol Spoiler: Ethanol Sourcing: 200 Proof Food Grade Ethanol 200 Proof Food Grade Ethanol Can be purchased easily on through vendors, Concentration is important in Formulation. 20% Water Spoiler: Water Sourcing: Purified Water should be Exclusively Used Just got to your local New Delhi Convenience store View attachment 5413502 7% Butylene Glycol Spoiler: Butylene Glycol Sourcing: Butylene Glycol, Penetration Enhancer and Solubilizer Easy to buy literally get off amazon, 1,3-Ratio Butylene Glycol Cosmetic Grade (250 mL / 8.45 Oz) 1% Sepimax Zen Spoiler: Sepimax Zen Sourcing: Used in creation of Aqueous Gel Topicals Sepimax Zen Raw Polymer Powder (FORMULA B) 5% Dimethyl Isossorbide(DMI) Spoiler: Dimethyl Isossorbide Sourcing: Low Irritant Penetration Enhancer Dimethyl Isosorbide (DMI) Ethyl Alcohol: Most Often used as a solvent for APIs due to it's exceptional ability to solute oil and water based substances, it's a rapid evaporator due to it's structural similarity to isopropyl alcohol, making it a great choice for cosmetic appliances.​ Water: Water is present in most Topical Formulations serving as a solvent for many APIs and as a penetration enhancer because of the skins natural absorption of water, usually paired with co solvents because of low water solubility sometimes found in APIs​ Butylene Glycol: Alcohol based Excipient is a Primary Solvent, Humectant, antibacterial agent, and an emolient, found in water based systems as a substitute for propylene glycol, and is chosen in formulations based on serums, creams, and hair product creation.​ Sepimax Zen: View attachment 5412763 (proprietary product no cool chemical image) Sepimax Zen(Polyacrylate Crosspolymer-6) is a solution that enables the formulation to have enhanced thickening and stabilization, most carrier types(gels, creams, emulsions) are compatible with Sepimax Zen.​ (FORMULA B) Dimethyl Isossorbide: View attachment 5412973 Dimethyl Isosorbide(DMI) is a co-solvent used to carry APIs more evenly across the skin, its incredibly tolerated low irritant solvent that is great for high Molecular weight APIs because of it's lightness and stabilization capabilities.​

(Formula A and B listing Differ for ingredients, simply based off the Clinical Trial, only difference is DMI is added and the water concentration is dropped to 15% in Formula B
Formula B might be preferred for enhanced Penetration)



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Formulation Instructions:​

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Conclusion and Extra:​

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SIK Inhibitors are an interesting group of kinase inhibitors that have numerous purposes in pharmacotherapy, with albeit mild implications of influence, they still hold presidence in therapeutic application ranging from Osteoporosis therapy to Fat loss Medication. SIK-2 Inhibitors have shown great promise in changing skin pigmentation for extended periods of time, up to 4 weeks potentially more. Moreover, It's a Topical agent so it's ease of use might make it another choice for Tanning, other benefits that have been observed is it's ability to enhance DNA repair in keratinocytes and fibroblasts, and decrease expression of the MMP-1; a key marker for photoaging. Overall with no worrisome side effects brought to light regarding inhibition effects on neighboring pathways, SIK2 inhibitors are a great alternative to Melontan I/II, also one of the few ways soulless gingers can get a tan jfl.​

If the reception on this Guide does well i'll likely make another one on a different topic lmk if u guys would like that thread took genuinely a week to make ​

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@Feuerwehr @Paul.jnxy @Regret @Scarlet @Stalker
@nwed @shedontluv-U @Anakin. @Daquavius Jr. 3rd @Lexapro @negative @nestivv @Scandi. @76.1 @alurmo @pleasevanity @buccalfatremoval @Askinov

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dnr tranny

 

[Shirobon]

dnr tranny

im lost
did u just call me a tranny
and then dnr me

 

[GandysOrbitals]

BUMPINGTON

 

[Mr. Squarepants]

I fell inlove with the formatting

 

[Shirobon]

I fell inlove with the formatting

u jokin or na

 

[Mr. Squarepants]

u jokin or na

Nah its goated

 

[shedontluv-U]

Awesome threads op

 

[Fynn]

mirin the high effort bhai

 

[Fynn]

bump

 

[Shirobon]

mirin the high effort bhai

Awesome threads op

thx brahs