Design, synthesis, and biological evaluation of 3,4-dihydroquinolin-2(1 H)-one and 1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors

Jailall Ramnauth, Joanne Speed, Shawn P. Maddaford, Peter Dove, Subhash C. Annedi, Paul Renton, Suman Rakhit, John Andrews, Sarah Silverman, Gabriela Mladenova, Salvatore Zinghini, Sheela Nair, Concettina Catalano, David K.H. Lee, Milena De Felice, Frank Porreca

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Neuronal nitric oxide synthase (nNOS) inhibitors are effective in preclinical models of many neurological disorders. In this study, two related series of compounds, 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4- tetrahydroquinoline, containing a 6-substituted thiophene amidine group were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). A structure-activity relationship (SAR) study led to the identification of a number of potent and selective nNOS inhibitors. Furthermore, a few representative compounds were shown to possess druglike properties, features that are often difficult to achieve when designing nNOS inhibitors. Compound (S)-35, with excellent potency and selectivity for nNOS, was shown to fully reverse thermal hyperalgesia when given to rats at a dose of 30 mg/kg intraperitonieally (ip) in the L5/L6 spinal nerve ligation model of neuropathic pain (Chung model). In addition, this compound reduced tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in a rat model of dural inflammation relevant to migraine pain.

Original languageEnglish (US)
Pages (from-to)5562-5575
Number of pages14
JournalJournal of Medicinal Chemistry
Volume54
Issue number15
DOIs
StatePublished - Aug 11 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Ramnauth, J., Speed, J., Maddaford, S. P., Dove, P., Annedi, S. C., Renton, P., Rakhit, S., Andrews, J., Silverman, S., Mladenova, G., Zinghini, S., Nair, S., Catalano, C., Lee, D. K. H., De Felice, M., & Porreca, F. (2011). Design, synthesis, and biological evaluation of 3,4-dihydroquinolin-2(1 H)-one and 1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors. Journal of Medicinal Chemistry, 54(15), 5562-5575. https://doi.org/10.1021/jm200648s