Discovery and Optimization of Highly Potent and Selective ATR Antagonists to Relieve Peripheral Neuropathic Pain.

The angiotensin II type 2 receptor (ATR) has attracted much attention as a potential target for the relief of neuropathic pain, which represents an area of unmet clinical need. A series of 1,2,3,4-tetrahydroisoquinolines with a benzoxazole side-chain were discovered as potent ATR antagonists. Rational optimization resulted in compound , which demonstrated both excellent antagonistic activity against ATR and analgesic efficacy in a rat chronic constriction injury model. Its favorable physicochemical properties and oral bioavailability make it a promising therapeutic candidate for neuropathic pain.