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 1 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.

本研究首次鉴定出人类免疫缺陷病毒（HIV）蛋白酶抑制剂安普那韦（amprenavir）可作为选择性大麻素受体2（CB2）激动剂，并针对该外周限制性骨架开展构效关系（SAR）研究，以将其重新开发为兼具高CB2受体活性与中枢神经系统（CNS）暴露特性的化合物。该研究得到的化合物展现出优异的CB2受体激动活性（半最大效应浓度EC50 < 1 nM）、对CB1受体的高选择性，以及良好的预测性膜通透性与低P-糖蛋白（P-gp）外排活性。选取部分化合物开展大鼠静脉给药（i.v.）组合实验，多款新型安普那韦类似物展现出良好的半衰期（t1/2 > 2小时）、中等程度的血浆清除率，以及可观的脑部暴露量。此外，本研究结合分子动力学（MD）模拟开展全柔性蛋白-配体对接研究，以此预测高活性类似物VU6077967与CB2受体最可能的结合模式，并为该化合物系列相较于CB1受体的选择性差异提供理论依据。