Abstact

Allosteric inhibitors of HIV-1 integrase offer a promising approach to block an essential process in HIV-1 replication and offer a new strategy for HIV treatment. During the course of our drug discovery investigations, we identified novel allosteric HIV-1 integrase inhibitor 1 which has a conformationally constrained spiro indane scaffold. Our subsequent medicinal chemistry efforts using a structure-based drug design focused on the efficacies of related compound 5 against not only the wild type enzyme but also enzymes with polymorphisms and resistance mutations. As a result, we identified compound 38 f, which exhibited the desired efficacy against major polymorphisms and resistance mutations (EC(50)(WT) = 0.0040 muM, EC(50)(T124N) = 0.0048 muM, EC(50)(T125A) = 0.0038 muM, EC(50)(A128T) = 0.0057 muM), potent anti-HIV activity in the human serum assay (EC(50)(HS50%) = 0.091 muM), and preferable PK profiles in rats (Cl(tot) = 0.017 L/h/kg, MRT = 12.5 h, BA = 71.4 %).