GSK3186899

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

GSK3186899 是一种 Cdc2 相关激酶 12 抑制剂，对杜氏乳杆菌的 EC50 为 1.4 μM。

GSK3186899 is an inhibitor of Cdc2-related kinase 12 with an EC50 of 1.4 μM for L. donovani.(In Vitro):GSK3186899 is active in cidal axenic amastigote assay with an EC50 value of 0.1 μM. GSK3186899 shows good selectivity against mammalian THP-1 host cells (EC50 value > 50 μM). GSK3186899 exhibits a less than 10-fold variation in potency against a panel of Leishmania-derived lines. GSK3186899 is more active using human peripheral blood mononuclear cells as the host cells.(In Vivo):In the mouse model of infection, GSK3186899 (25 mg/kg; orally) reduces parasite levels by 99%. The efficacy of treatment is dependent on dose, frequency, and duration (10 days better than 5). There are no notable adverse effects in a rat seven-day repeat-dose oral toxicity study with respect to clinical chemistry and histopathology at all doses tested.

GSK3186899 (Compound 7) is active against L. donovani in an intra-macrophage assay with an EC50 value of 1.4 μM, and shows good selectivity against mammalian THP-1 host cells (EC50 value>50 μM). This is not as potent as reported data for amphotericin B (EC50 value of 0.07 μM in the intra-macrophage assay), but is comparable to the clinically used drugs miltefosine and paromomycin (EC50 values of 0.9 μM and 6.6 μM, respectively). GSK3186899 is also active in cidal axenic amastigote assay (EC50 value of 0.1 μM). At a concentration of 0.2 μM, GSK3186899 is cytocidal at 96 h; increasing the concentration to 1.8 μM reduced this time to 48 h. GSK3186899 demonstrates a less than 10-fold variation in potency against a panel of Leishmania-derived lines. GSK3186899 is also more active in a panel of Leishmania lines using human peripheral blood mononuclear cells as the host cells.

In the mouse model of infection, GSK3186899 demonstrates comparable activity to the front-line drug miltefosine, reducing parasite levels by 99% when dosed orally twice a day for 10 days at 25 mg/kg. The efficacy of treatment is dependent on dose, frequency, and duration (10 days better than 5). The non-clinical safety data for GSK3186899 suggests a suitable therapeutic window for progression into regulatory preclinical studies. Non-GLP preclinical assessment of cardiovascular effects and genotoxicity does not reveal any issues that would prevent further development. In addition, there are no notable adverse effects in a rat seven-day repeat-dose oral toxicity study with respect to clinical chemistry and histopathology at all doses tested. Both the in vivo efficacy and safety profile of GSK3186899 support progression to definitive safety studies.

DDD-853651 | 3,3,3-trifluoro-N-[4-[[3-[(2R)-2-methylmorpholin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]cyclohexyl]propane-1-sulfonamide

Microbiology/Virology

Parasite

HIV-1

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1972617-87-0

491.53

C19H28F3N7O3S

>98% (HPLC)

In Vitro:?DMSO : 250 mg/mL (508.62 mM)

C[C@H]1CN(CCO1)c1n[nH]c2nc(N[C@H]3CC[C@@H](CC3)NS(=O)(=O)CCC(F)(F)F)ncc12

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(-20℃)

With Ice Pack

≥ 2 years