HIV PROTEASE INHIBITOR HOE/BAY-793, STRUCTURE-ACTIVITY-RELATIONSHIPS IN A SERIES OF C-2-SYMMETRICAL DIOLS

A detailed structure-activity relationship of C-2-symmetric diol inhibitors of HIV-1 protease leads to inhibitor 6 (HOE/BAY 793) which is outstanding in the inhibition of the enzyme and in the inhibition of viral replication in HN infected cell culture (IC50:0.3 nM; EC(50):3 nM). There are well defined steric requirements for the design of the side chains P1-P3 of the inhibitors. In addition, all three side chains need to be lipophilic. While the enzyme tolerates hydrophilic substituents in some cases, drastic reductions in anti-HIV activity are observed in cell culture, most likely due to insufficient cell penetration.