Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine- based selective inhibitors of human neuronal nitric oxide synthase (nNOS)

Subhash C. Annedi, Jailall Ramnauth, Michele Cossette, Shawn P. Maddaford, Peter Dove, Suman Rakhit, John S. Andrews, Frank Porreca

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure-activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzo[b]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (±)-39, and (±)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K + channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels).

Original languageEnglish (US)
Pages (from-to)2510-2513
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number7
DOIs
StatePublished - Apr 1 2012

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Keywords

  • 2,3,4,5-Tetrahydro-1H-benzo[b]azepine derivatives
  • Neuropathic pain
  • Nitric oxide
  • Nitric oxide synthase
  • Selective neuronal nitric oxide synthase inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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