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 Citations (Scopus)

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

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Nitric Oxide Synthase Type I
Amidines
Nitric Oxide Synthase Type III
Derivatives
Drug interactions
Thiophenes
Spinal Nerves
Hyperalgesia
Guanidine
Neuralgia
Nitric Oxide Synthase Type II
Drug Interactions
Human Activities
Nitric Oxide Synthase
Cytochrome P-450 Enzyme System
Amines
Ligation
Protein Isoforms
Pharmaceutical Preparations
indole

Keywords

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

3,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase (nNOS) inhibitors. / Annedi, Subhash C.; Maddaford, Shawn P.; Ramnauth, Jailall; Renton, Paul; Speed, Joanne; Rakhit, Suman; Andrews, John S.; Porreca, Frank.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 5, 01.03.2012, p. 1980-1984.

Research output: Contribution to journalArticle

Annedi, Subhash C. ; Maddaford, Shawn P. ; Ramnauth, Jailall ; Renton, Paul ; Speed, Joanne ; Rakhit, Suman ; Andrews, John S. ; Porreca, Frank. / 3,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase (nNOS) inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 5. pp. 1980-1984.
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