8FGT

Structure of human endothelial nitric oxide synthase heme domain in complex with 6-(2,3-difluoro-5-(2-(4-methylpiperazin-1-yl)ethyl)phenethyl)-4-methylpyridin-2-amine

Summary for 8FGT

• Entry DOI: 10.2210/pdb8fgt/pdb
• Descriptor: Nitric oxide synthase, endothelial, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (10 entities in total)
• Functional Keywords: nitric oxide synthase inhibitor, heme enzyme, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 206226.87

Authors

Li, H.,Poulos, T.L. (deposition date: 2022-12-12, release date: 2023-10-11)

Primary citation

Vasu, D.,Do, H.T.,Li, H.,Hardy, C.D.,Awasthi, A.,Poulos, T.L.,Silverman, R.B.
Potent, Selective, and Membrane Permeable 2-Amino-4-Substituted Pyridine-Based Neuronal Nitric Oxide Synthase Inhibitors.
J.Med.Chem., 66:9934-9953, 2023

PubMed Abstract: A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS), based on a difluorobenzene ring linked to a 2-aminopyridine scaffold with different functionalities at the 4-position, is reported. In our efforts to develop novel nNOS inhibitors for the treatment of neurodegenerative diseases, we discovered , which showed excellent potency toward both rat ( 15 nM) and human nNOS ( 19 nM), with 1075-fold selectivity over human eNOS and 115-fold selectivity over human iNOS. also showed excellent permeability ( = 13.7 × 10 cm s), a low efflux ratio (ER 0.48), along with good metabolic stability in mouse and human liver microsomes, with half-lives of 29 and >60 min, respectively. X-ray cocrystal structures of inhibitors bound with three NOS enzymes, namely, rat nNOS, human nNOS, and human eNOS, revealed detailed structure-activity relationships for the observed potency, selectivity, and permeability properties of the inhibitors.

PubMed: 37433128
DOI: 10.1021/acs.jmedchem.3c00782

Experimental method

X-RAY DIFFRACTION (1.9 Å)