Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker

Heng Yen Wang, Yajuan Qin, Huiying Li, Linda J. Roman, Pavel Martásek, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability.

Original languageEnglish (US)
Pages (from-to)4913-4925
Number of pages13
JournalJournal of Medicinal Chemistry
Volume59
Issue number10
DOIs
StatePublished - May 26 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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