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

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

  • J Med Chem. 2026 Feb 26;69(4):4187-4207. doi: 10.1021/acs.jmedchem.5c02796.
Daniel H Haymer 1 2,  Renn A Duncan 1 2,  Alice L Rodriguez 1 2,  Allie Han 1 2,  Richard J Lindsay 2 3,  N Kithmini Wijesiri 2 3,  Analisa Thompson Gray 1 2,  Srinivasan Krishnan 1 2,  Aidong Qi 1 2,  Benjamin P Brown 2 3,  Olivier Boutaud 1 2 4,  Darren W Engers 1 2,  Carrie K Jones 1 2 5 4,  Colleen M Niswender 1 2 5 6 7 4,  Craig W Lindsley 1 2 8 4,  Aaron M Bender 1 2
Affiliations

Affiliations

  • 1 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2 Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 3 Center for AI in Protein Dynamics, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 4 Vanderbilt Institute for Therapeutic Advances, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 5 Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6 Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 7 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 8 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 41642702 DOI: 10.1021/acs.jmedchem.5c02796
Abstract

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.

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