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 t1/2 (>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.