7TSP

Structure of human endothelial nitric oxide synthase heme domain in complex with 6-(3-(4,4-difluoropiperidin-1-yl)prop-1-yn-1-yl)-4-methylpyridin-2-amine

7TSP の概要

• エントリーDOI: 10.2210/pdb7tsp/pdb
• 分子名称: Nitric oxide synthase, endothelial, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (10 entities in total)
• 機能のキーワード: nitric oxide synthase inhibitor, heme enzyme, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 205606.01

構造登録者

Li, H.,Poulos, T.L. (登録日: 2022-01-31, 公開日: 2022-07-13, 最終更新日: 2023-10-18)

主引用文献

Vasu, D.,Li, H.,Hardy, C.D.,Poulos, T.L.,Silverman, R.B.
2-Aminopyridines with a shortened amino sidechain as potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors.
Bioorg.Med.Chem., 69:116878-116878, 2022

PubMed Abstract: A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS) based on the 2-aminopyridine scaffold with a shortened amino sidechain is reported. A rapid and simple protocol was developed to access these inhibitors in excellent yields. Neuronal nitric oxide synthase (nNOS) is a novel therapeutic target for the treatment of various neurological disorders. The major challenges in designing nNOS inhibitors in humans focus on potency, selectivity over other isoforms of nitric oxide synthases (NOSs), and blood-brain barrier permeability. In this context, we discovered a promising inhibitor, 6-(3-(4,4-difluoropiperidin-1-yl)propyl)-4-methylpyridin-2-amine dihydrochloride, that exhibits excellent potency for rat (K = 46 nM) and human nNOS (K = 48 nM), respectively, with 388-fold human eNOS and 135-fold human iNOS selectivity. It also displayed excellent permeability (P = 17.3 × 10 cm s) through a parallel artificial membrane permeability assay, a model for blood-brain permeability. We found that increasing lipophilicity by incorporation of fluorine atoms on the backbone of the inhibitors significantly increased potential blood-brain barrier permeability. In addition to measuring potency, isoform selectivity, and permeability of NOS inhibitors, we also explored structure-activity relationships via structures of key inhibitors complexed to various isoforms of nitric oxide synthases.

PubMed: 35772285
DOI: 10.1016/j.bmc.2022.116878

実験手法

X-RAY DIFFRACTION (2 Å)