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 Citations (Scopus)

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

Fingerprint

Azepines
Nitric Oxide Synthase Type I
Spinal Nerves
Neuralgia
Structure-Activity Relationship
Ion Channels
Nitric Oxide Synthase
Amines
Ligation
Assays
Throughput
Pharmacology
Derivatives
Safety
Therapeutics

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

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

Cite this

Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine- based selective inhibitors of human neuronal nitric oxide synthase (nNOS). / Annedi, Subhash C.; Ramnauth, Jailall; Cossette, Michele; Maddaford, Shawn P.; Dove, Peter; Rakhit, Suman; Andrews, John S.; Porreca, Frank.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 7, 01.04.2012, p. 2510-2513.

Research output: Contribution to journalArticle

Annedi, Subhash C. ; Ramnauth, Jailall ; Cossette, Michele ; Maddaford, Shawn P. ; Dove, Peter ; Rakhit, Suman ; Andrews, John S. ; Porreca, Frank. / Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine- based selective inhibitors of human neuronal nitric oxide synthase (nNOS). In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 7. pp. 2510-2513.
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