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

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.
AuthorsJailall 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
JournalJournal of medicinal chemistry (J Med Chem) Vol. 54 Issue 15 Pg. 5562-75 (Aug 11 2011) ISSN: 1520-4804 [Electronic] United States
PMID21699209 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Quinolines
  • 1,2,3,4-tetrahydroquinoline
  • NOS1 protein, human
  • Nitric Oxide Synthase Type I
Topics
  • Animals
  • Humans
  • Hyperalgesia (drug therapy)
  • Male
  • Migraine Disorders (drug therapy)
  • Neuralgia (drug therapy)
  • Nitric Oxide Synthase Type I (antagonists & inhibitors)
  • Quinolines (chemical synthesis, pharmacokinetics, therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

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