9Q58

Structure of human endothelial nitric oxide synthase heme domain bound with 6-((5-(2-(4,4-difluoropiperidin-1-yl)ethyl-2,3-difluorophenoxy)methyl)-4-methylpyridin-2-amine

これはPDB形式変換不可エントリーです。

9Q58 の概要

• エントリーDOI: 10.2210/pdb9q58/pdb
• 分子名称: Nitric oxide synthase 3, CALCIUM ION, PROTOPORPHYRIN IX CONTAINING FE, ... (11 entities in total)
• 機能のキーワード: nitric oxide synthase inhibitor binding, oxidoreductase-inhibitor complex, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 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: 205479.75

構造登録者

Li, H.,Poulos, T.L. (登録日: 2025-08-20, 公開日: 2025-09-10, 最終更新日: 2026-02-25)

主引用文献

Ansari, A.,Chrzanowski, R.T.,Li, H.,Hardy, C.D.,Awasthi, A.,Poulos, T.L.,Silverman, R.B.
Potent, Selective, and Brain Penetrant Ether-Linked 2-Aminopyridine Inhibitors of Human Neuronal Nitric Oxide Synthase with Excellent Oral Bioavailability.
J.Med.Chem., 69:3506-3518, 2026

PubMed Abstract: Neuronal nitric oxide synthase (nNOS) is a therapeutic target for the treatment of various neurological disorders and for melanoma. As part of our ongoing efforts to develop potent and selective nNOS inhibitors, we modified our previously reported compound to by introducing an ether linker, leading to a new series of ether-linked 2-aminopyridine-based compounds that exhibit high potency, isoform selectivity, and membrane permeability. Among them, lead compound inhibits human nNOS with a of 25 nM and exhibits 2300-fold selectivity over human endothelial NOS (eNOS) while also displaying high effective permeability in the parallel artificial membrane permeability assay for the blood-brain barrier (PAMPA-BBB) assay ( = 16.67 × 10 cm/s), indicating favorable blood-brain barrier penetration. Pharmacokinetic evaluation confirmed the brain penetrance of and demonstrated a high oral bioavailability (77%). Moreover, the X-ray crystal structures of representative compounds bound to three NOS isoforms (hnNOS, rnNOS, and heNOS) revealed key binding interactions that contribute to both potency and selectivity.

PubMed: 41630196
DOI: 10.1021/acs.jmedchem.5c03568

実験手法

X-RAY DIFFRACTION (2.03 Å)