Discovery and optimization of novel and potent allosteric HIV-1 integrase inhibitors with a spiro[indene] moiety

Abstract

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 (EC₅₀(WT) = 0.0040 μM, EC₅₀(T124N) = 0.0048 μM, EC₅₀(T125A) = 0.0038 μM, EC₅₀(A128T) = 0.0057 μM), potent anti-HIV activity in the human serum assay (EC₅₀(HS50%) = 0.091 μM), and preferable PK profiles in rats (Cl_tot = 0.017 L/h/kg, MRT = 12.5 h, BA = 71.4 %).

Keywords: Allosteric inhibitor; HIV-1 integrase; LEDGF/p75; LEDGINs; Structure-based drug design.