Discovery of N -(3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H -indol-6-yl) thiophene-2-carboximidamide as a selective inhibitor of human neuronal nitric oxide synthase (nNOS) for the treatment of pain

Subhash C. Annedi, Shawn P. Maddaford, Gabriela Mladenova, Jailall Ramnauth, Suman Rakhit, John S. Andrews, David K.H. Lee, Dongqin Zhang, Frank Porreca, David Bunton, Lee Christie

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

3,6-Disubstituted indole derivatives were designed, synthesized, and evaluated as inhibitors of human nitric oxide synthase (NOS). Bulky amine containing substitution on the 3-position of the indole ring such as an azabicyclic system showed better selectivity over 5- and 6-membered cyclic amine substitutions. Compound (-)-19 showed the best selectivity for neuronal NOS over endothelial NOS (90-fold) and inducible NOS (309-fold) among the current series. Compounds 16 and (-)-19 were shown to be either inactive or very weak inhibitors of human cytochrome P450 enzymes, indicating a low potential for drug-drug interactions. Compound 16 was shown to reverse thermal hyperalgesia in vivo in the Chung model of neuropathic pain. Compound 16 was also devoid of any significant vasoconstrictive effect in human coronary arteries, associated with the inhibition of human eNOS. These results suggest that 16 may be a useful tool for evaluating the potential role of selective nNOS inhibitors in the treatment of pain such as migraine and CTTH.

Original languageEnglish (US)
Pages (from-to)7408-7416
Number of pages9
JournalJournal of Medicinal Chemistry
Volume54
Issue number20
DOIs
StatePublished - Oct 27 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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