Tang, Jun, Jones, Stacey A., Jeffrey, Jerry L., Miranda, Sonia R., Galardi, Cristin M., Irlbeck, David M., Brown, Kevin W., McDanal, Charlene B., and Johns, Brian A.
A new class of betulin-derived α-keto amides was identified as HIV-1 maturation inhibitors. Through lead optimization, GSK8999 was identified with IC 50 values of 17 nM, 23 nM, 25 nM, and 8 nM 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. [ABSTRACT FROM AUTHOR]