Symmetric double-headed aminopyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase

Fengtian Xue, Jianguo Fang, Silvia L. Delker, Huiying Li, Pavel Martásek, Linda J. Roman, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

We report novel neuronal nitric oxide synthase (nNOS) inhibitors based on a symmetric double-headed aminopyridine scaffold. The inhibitors were designed from crystal structures of leads 1 and 2 (Delker, S. L.; Ji, H.; Li, H.; Jamal, J.; Fang, J.; Xue, F.; Silverman, R. B.; Poulos, T. L.Unexpected binding modes of nitric oxide synthase inhibitors effective in the prevention of cerebral palsy. J. Am. Chem. Soc. 2010, 132, 5437-5442) and synthesized using a highly efficient route. The best inhibitor, 3j, showed low nanomolar inhibitory potency and modest isoform selectivity. It also exhibited enhanced membrane permeability. Inhibitor 3j binds to both the substrate site and the pterin site in nNOS but only to the substrate site in eNOS. These compounds provide a basis for further development of novel, potent, isoform selective, and bioavailable inhibitors for nNOS.

Original languageEnglish (US)
Pages (from-to)2039-2048
Number of pages10
JournalJournal of Medicinal Chemistry
Volume54
Issue number7
DOIs
StatePublished - Apr 14 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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