3,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase (nNOS) inhibitors

Subhash C. Annedi, Shawn P. Maddaford, Jailall Ramnauth, Paul Renton, Joanne Speed, Suman Rakhit, John S. Andrews, Frank Porreca

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

A series of 3,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). Various guanidine isosteric groups were explored at the 5-position of the indole ring, while keeping the basic amine side chain such as N-methylpiperidine ring, fixed at the 3-position of the indole ring. Compounds having 2-thiophene amidine and 2-furanyl amidine groups (7, 8, 10 and 12) showed increased activity for human neuronal NOS and good selectivity over endothelial and inducible NOS isoforms. Compound 8 was shown to reverse (10 mg/kg, ip) thermal hyperalgesia in the L 5/L 6 spinal nerve ligation (neuropathic pain) model and was devoid of any significant drug-drug interaction potential due to cytochrome P450 inhibition or cardiovascular liabilities associated with the inhibition of endothelial NOS.

Original languageEnglish (US)
Pages (from-to)1980-1984
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number5
DOIs
StatePublished - Mar 1 2012

Keywords

  • 3,5-Disubstituted indole derivatives
  • Migraine
  • Neuropathic pain
  • Nitric oxide
  • 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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