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Purity: ≥98%
GSK3186899 (also known as DDD-853651) is a novel and potent inhibitor of cdc-2-related kinase 12 (CRK12), with an EC50 of 1.4 μM for L. donovani in an intra-macrophage assay. Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. GSK3186899 is an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. It is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.
| ln Vitro |
GSK3186899 (Compound 7) shown activity against L. Donovani demonstrated high selectivity against mammalian THP-1 host cells (EC50 value >50 μM) in an intramacrophage experiment, with an EC50 value of 1.4 μM. While this is compatible with the clinically utilized medications miltefosine and paromomycin (EC50 values of 0.9 μM and 6.6 μM, respectively), it is not as valid as the data reported for amphotericin B (EC50 value of 0.07 μM in intramacrophage experiment). ) quite. In the cidal sterile amastigote assay, GSK3186899 exhibits activity as well (EC50 value of 0.1 μM). GSK3186899 was cytocidal in 96 hours at a dose of 0.2 μM; the duration was reduced to 48 hours at a concentration of 1.8 μM. When compared to a panel of strains produced from Leishmania, the efficacy of GSK3186899 varied by less than ten times. In a subset of Leishmania strains that utilize human peripheral blood mononuclear cells as their host cells, GSK3186899 is likewise more active [1].
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| ln Vivo |
GSK3186899, when administered orally twice daily for ten days at a dose of 25 mg/kg, reduced parasite levels by 99% in a mouse infection model, demonstrating action similar to that of the first-line medication miltefosine. Dosage, frequency, and length all affect how effective a treatment is (10 days is better than 5 days). For GSK3186899, nonclinical safety findings suggest a suitable therapeutic window for the initiation of regulatory preclinical investigations. Non-GLP preclinical analysis of genotoxicity and cardiovascular impacts did not identify any problems that would prevent further research. Furthermore, clinical chemistry and histopathology in a 7-day repeated-dose oral toxicity trial in rats revealed no appreciable side effects at any of the tested doses. Further conclusive safety studies are supported by the in vivo efficacy and safety profile of GSK3186899 [1].
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| References |
[1]. Wyllie S, et al. Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis. Nature. 2018 Aug;560(7717):192-197.
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| Molecular Formula |
C19H28F3N7O3S
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|---|---|
| Molecular Weight |
491.530932426453
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| Exact Mass |
491.192
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| CAS # |
1972617-87-0
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| PubChem CID |
122429808
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
33
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| Complexity |
746
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@H]1CN(CCO1)C2=NNC3=NC(=NC=C32)NC4CCC(CC4)NS(=O)(=O)CCC(F)(F)F
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| InChi Key |
RQWCISVRFNZHMJ-IHRRRGAJSA-N
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| InChi Code |
InChI=1S/C19H28F3N7O3S/c1-12-11-29(7-8-32-12)17-15-10-23-18(25-16(15)26-27-17)24-13-2-4-14(5-3-13)28-33(30,31)9-6-19(20,21)22/h10,12-14,28H,2-9,11H2,1H3,(H2,23,24,25,26,27)/t12-,13-,14-/m0/s1
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| Chemical Name |
3,3,3-Trifluoro-N-(trans-4-((3-((S)-2-methylmorpholino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)cyclohexyl)propane-1-sulfonamide
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| Synonyms |
GSK3186899; GSK 3186899; GSK-3186899; DDD-853651; DDD853651; DDD 853651
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~250 mg/mL (~508.62 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.23 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.23 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.23 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0345 mL | 10.1723 mL | 20.3446 mL | |
| 5 mM | 0.4069 mL | 2.0345 mL | 4.0689 mL | |
| 10 mM | 0.2034 mL | 1.0172 mL | 2.0345 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 Efficacy of compound 7 in a mouse model of VL.Nature.2018 Aug;560(7717):192-197. |
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 Studies to validate the molecular target of the pyrazolopyrimidine series.Nature.2018 Aug;560(7717):192-197. |
 Identification of cyclin dependent related kinases as targets of the pyrazolopyrimidine series using a chemoproteomic approach.Nature.2018 Aug;560(7717):192-197. |
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