Discovery and Optimization of Highly Potent and Selective AT2R Antagonists to Relieve Peripheral Neuropathic Pain

The angiotensin II type 2 receptor (AT2R) 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 AT2R antagonists. Rati...

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Bibliographic Details
Published in:ACS omega 2021-06, Vol.6 (23), p.15412-15420
Main Authors: Guo, Yanghui, Huang, Xiangui, Liao, Weiwei, Meng, Lichen, Xu, Daiwang, Ye, Cheng, Chen, Lei, Hu, Taishan
Format: Article
Language:English
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Summary:The angiotensin II type 2 receptor (AT2R) 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 AT2R antagonists. Rational optimization resulted in compound 15, which demonstrated both excellent antagonistic activity against AT2R in vitro 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.
ISSN:2470-1343
2470-1343
DOI:10.1021/acsomega.1c01866