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

Authors

Haymer DH Daniel H , Duncan RA Renn A , Rodriguez AL Alice L , Han A Allie , Lindsay RJ Richard J , Wijesiri NK N Kithmini , Thompson Gray A Analisa , Krishnan S Srinivasan , Qi A Aidong , Brown BP Benjamin P , Boutaud O Olivier , Engers DW Darren W , Jones CK Carrie K , Niswender CM Colleen M , Lindsley CW Craig W , Bender AM Aaron M .
Journal of medicinal chemistry. 2026 02 05; 69(4).
4187-4207

Abstract

Herein, we report the identification of the HIV protease inhibitor amprenavir as a selective cannabinoid receptor 2 (CB) agonist and describe structure-activity relationship (SAR) studies toward repurposing this peripherally restricted scaffold for high CB potency and CNS exposure. This exercise yielded compounds with exceptional CB potency (ECs <10 nM), no appreciable activity at the CB 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 (>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 CB and to provide a rationale for the observed selectivity of this series relative to CB.