Drug Repurposing: Conversion of the Peripherally Restricted HIV Protease Inhibitor Amprenavir to Potent, Selective, and CNS-Penetrant Agonists for the Cannabinoid Receptor 2

Herein, we report the identification of the HIV protease inhibitor amprenavir as a selective cannabinoid receptor 2 (CB₂) agonist and describe structure-activity relationship (SAR) studies toward repurposing this peripherally restricted scaffold for high CB₂ potency and CNS exposure. This exercise yielded compounds with exceptional CB₂ potency (EC₅₀s <10 nM), no appreciable activity at the CB₁ receptor, and high predicted permeability/low P-gp efflux activity. Selected compounds were profiled in rat i.v. dosing cassettes; several novel amprenavir analogues displayed good <i>t</i>_1/2 (>2 h), moderate plasma clearance, and appreciable brain exposure. Additionally, fully flexible protein-ligand docking studies with molecular dynamics (MD) simulations were used to predict the most likely mode of interaction of highly potent analogue VU6077967 with CB₂ and to provide a rationale for the observed selectivity of this series relative to CB₁.