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Structure-guided design of substituted biphenyl butanoic acid derivatives as Neprilysin inhibitors

Kawanami, Toshio, Karki, Rajeshri, Cody, Emma, Liu, Qian, Liang, Guiqing, Ksander, Gary, Schiering, Nikolaus, Gong, Yongjin, Coppola, Gary, Iwaki, Yuki, Sun, Robert, Neubert, Alan, Fan, Li, Ingles Ginesta, Sara, D'Arcy, Allan, Villard, Frederic, Ramage, Paul, Jeng, Arco, Leung-Chu, Jennifer, Liu, Jing, Beil, Michael, Fu, Fumin, Chen, Wei, Rigel, Dean, Cumin, Frederic, Wiesmann, Christian and Mogi, Muneto (2020) Structure-guided design of substituted biphenyl butanoic acid derivatives as Neprilysin inhibitors. ACS Medicinal Chemistry Letters, 11 (2). pp. 188-194. ISSN 1948-58751948-5875


Inhibition of neprilysin (NEP) is widely studied as a therapeutic target for the treatment of hypertension, heart failure and kidney disease. Sacubitril/valsartan (LCZ696) is a drug approved to reduce the risk of cardiovascular death in heart failure patients with reduced ejection fraction. LBQ657 is the active metabolite of sacubitril and an inhibitor of NEP. Previously, we have reported the crystal structure of NEP bound with LBQ657, whereby we noted the presence of a sub-site in S1’ that has not been explored before. We were also intrigued by the zinc coordination made by one of the carboxylic acids of LBQ657, leading us to explore alternative linkers to efficiently engage zinc for NEP inhibition. Structure-guided design culminated in the synthesis of selective, orally bioavailable and subnanomolar inhibitors of NEP. A 17-fold boost in biochemical potency was observed upon addition of a chlorine atom that occupied the newly found sub-site in S1’. We report herein the discov-ery and pre-clinical profiling of compound 13, which paved the path to our clinical candidate.

Item Type: Article
Keywords: Neprilysin, crystal structure, structure-based design, structure-activity relationship
Date Deposited: 07 Mar 2020 00:45
Last Modified: 07 Mar 2020 00:45


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