Tang Jun, Jones Stacey A, Jeffrey Jerry L, Miranda Sonia R, Galardi Cristin M, Irlbeck David M, Brown Kevin W, McDanal Charlene B, Johns Brian A
GlaxoSmithKline Research & Development, Infectious Diseases Therapy Area Unit, Research Triangle Park, NC 27709, USA.
GlaxoSmithKline Research & Development, Infectious Diseases Therapy Area Unit, Research Triangle Park, NC 27709, USA.
Bioorg Med Chem Lett. 2017 Jun 15;27(12):2689-2694. doi: 10.1016/j.bmcl.2017.04.042. Epub 2017 Apr 20.
A new class of betulin-derived α-keto amides was identified as HIV-1 maturation inhibitors. Through lead optimization, GSK8999 was identified with IC values of 17nM, 23nM, 25nM, and 8nM for wild type, Q369H, V370A, and T371A respectively. When tested in a panel of 62 HIV-1 isolates covering a diversity of CA-SP1 genotypes including A, AE, B, C, and G using a PBMC based assay, GSK8999 was potent against 57 of 62 isolates demonstrating an improvement over the first generation maturation inhibitor BVM. The data disclosed here also demonstrated that the new α-keto amide GSK8999 has a mechanism of action consistent with inhibition of the proteolytic cleavage of CA-SP1.
一类新的桦木醇衍生的α-酮酰胺被鉴定为HIV-1成熟抑制剂。通过先导化合物优化，确定了GSK8999，其对野生型、Q369H、V370A和T371A的IC值分别为17nM、23nM、25nM和8nM。当使用基于外周血单核细胞（PBMC）的检测方法在一组涵盖多种CA-SP1基因型（包括A、AE、B、C和G）的62株HIV-1分离株中进行测试时，GSK8999对62株分离株中的57株具有强效作用，显示出优于第一代成熟抑制剂BVM的效果。此处披露的数据还表明，新型α-酮酰胺GSK8999的作用机制与抑制CA-SP1的蛋白水解切割一致。
