Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: Structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies

Recently, we designed a series of novel HIV-1 protease inhibitors incorporating a stereochemically defined bicyclic fused cyclopentyl (Cp-THF) urethane as the high affinity P2-ligand. Inhibitor 1 with this P2-ligand has shown very impressive potency against multi-drug-resistant clinical isolates. Based upon the 1-bound HIV-1 protease X-ray structure, we have now designed and synthesized a number of meso-bicyclic ligands which can conceivably interact similarly to the Cp-THF ligand. The design of meso-ligands is quite attractive as they do not contain any stereocenters. Inhibitors incorporating urethanes of bicyclic-1,3-dioxolane and bicyclic-1,4-dioxane have shown potent enzyme inhibitory and antiviral activities. Inhibitor 2 (K_i = 0.11 nM; IC₅₀ = 3.8 nM) displayed very potent antiviral activity in this series. While inhibitor 3 showed comparable enzyme inhibitory activity (K _i = 0.18 nM) its antiviral activity (IC₅₀ = 170 nM) was significantly weaker than inhibitor 2. Inhibitor 2 maintained an antiviral potency against a series of multi-drug resistant clinical isolates comparable to amprenavir. A protein-ligand X-ray structure of 3-bound HIV-1 protease revealed a number of key hydrogen bonding interactions at the S2-subsite. We have created an active model of inhibitor 2 based upon this X-ray structure.