6THP

Neprilysin in complex with the inhibitor (R)-4-(1-carboxy-3-(3'-chlorobiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoic acid

Summary for 6THP

• Entry DOI: 10.2210/pdb6thp/pdb
• Descriptor: Neprilysin, 2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 161731.16

Authors

Schiering, N.,Wiesmann, C. (deposition date: 2019-11-21, release date: 2020-02-12, Last modification date: 2024-11-13)

Primary citation

Kawanami, T.,Karki, R.G.,Cody, E.,Liu, Q.,Liang, G.,Ksander, G.M.,Rigel, D.F.,Schiering, N.,Gong, Y.,Coppola, G.M.,Iwaki, Y.,Sun, R.,Neubert, A.,Fan, L.,Ingles, S.,D'Arcy, A.,Villard, F.,Ramage, P.,Jeng, A.Y.,Leung-Chu, J.,Liu, J.,Beil, M.,Fu, F.,Chen, W.,Cumin, F.,Wiesmann, C.,Mogi, M.
Structure-Guided Design of Substituted Biphenyl Butanoic Acid Derivatives as Neprilysin Inhibitors.
Acs Med.Chem.Lett., 11:188-194, 2020

PubMed Abstract: 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 , which paved the path to our clinical candidate.

PubMed: 32071687
DOI: 10.1021/acsmedchemlett.9b00578

Experimental method

X-RAY DIFFRACTION (2.54 Å)