Open AccessStructure-Guided Design of Substituted Biphenyl Butanoic Acid Derivatives as Neprilysin Inhibitors
Author(s) -
Toshio Kawanami,
Rajeshri G. Karki,
Emma Cody,
Qian Liu,
Guiqing Liang,
Gary M. Ksander,
Dean F. Rigel,
Nikolaus Schiering,
Yongjin Gong,
Gary M. Coppola,
Yuki Iwaki,
Robert Sun,
Alan D. Neubert,
Lei Fan,
Sara Ingles,
Allan D’Arcy,
Frédéric Villard,
Paul Ramage,
Arco Y. Jeng,
Jennifer Leung-Chu,
Jing Liu,
Michael E. Beil,
Fumin Fu,
Wei Chen,
Frédéric Cumin,
Christian Wiesmann,
Muneto Mogi
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00578
Subject(s) - sacubitril , chemistry , neprilysin , pharmacology , stereochemistry , medicine , biochemistry , enzyme
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 subsite 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 subsite in S1'. We report herein the discovery and preclinical profiling of compound 13 , which paved the path to our clinical candidate.