Structure-Guided Design of Substituted Biphenyl Butanoic Acid Derivatives as Neprilysin Inhibitors.

Autor:	Kawanami T; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Karki RG; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Cody E; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Liu Q; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Liang G; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Ksander GM; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Rigel DF; Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936-1080, United States., Schiering N; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Gong Y; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Coppola GM; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Iwaki Y; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Sun R; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Neubert A; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Fan L; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States., Ingles S; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., D'Arcy A; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Villard F; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Ramage P; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Jeng AY; Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936-1080, United States., Leung-Chu J; Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936-1080, United States., Liu J; Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936-1080, United States., Beil M; Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936-1080, United States., Fu F; Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936-1080, United States., Chen W; Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936-1080, United States., Cumin F; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Wiesmann C; Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland., Mogi M; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2020 Jan 27; Vol. 11 (2), pp. 188-194. Date of Electronic Publication: 2020 Jan 27 (Print Publication: 2020).
DOI:	10.1021/acsmedchemlett.9b00578
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest. (Copyright © 2020 American Chemical Society.)
Databáze:	MEDLINE
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