Discovery of cis - N -(1-(4-(methylamino)cyclohexyl)indolin-6-yl)thiophene- 2-carboximidamide: A 1,6-disubstituted indoline derivative as a highly selective inhibitor of human neuronal nitric oxide synthase (nNOS) without any cardiovascular liabilities

Subhash C. Annedi, Jailall Ramnauth, Shawn P. Maddaford, Paul Renton, Suman Rakhit, Gabriela Mladenova, Peter Dove, Sarah Silverman, John S. Andrews, Milena D. Felice, Frank Porreca

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

A series of 1,6-disubstituted indoline derivatives were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS) designed to mitigate the cardiovascular liabilities associated with previously reported tetrahydroquinoline-based selective neuronal NOS inhibitors due to higher lipophilicity (J. Med. Chem. 2011, 54, 5562-5575). This new series produced similar potency and selectivity among the NOS isoforms and was devoid of any cardiovascular liabilities associated with QT prolongation due to hERG activity or endothelial NOS mediated vasoconstriction effect. The SAR studies led to the identification of cis-45, which was shown to reverse thermal hyperalgesia in vivo in the spinal nerve ligation model of neuropathic pain with excellent safety profile (off-target activities at 80 CNS related receptors/ion channels/transporters). The results presented in this report make cis-45 as an ideal tool for evaluating the potential role of selective nNOS inhibitors in CNS related disorders where excess NO produced by nNOS is thought to play a crucial role.

Original languageEnglish (US)
Pages (from-to)943-955
Number of pages13
JournalJournal of Medicinal Chemistry
Volume55
Issue number2
DOIs
StatePublished - Jan 26 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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