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
  • 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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