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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 11, 2011
• 年：2011
• 卷：54
• 期：15
• 页码：5562-5575
• 全文大小：1087K
• 年卷期：v.54,no.15(August 11, 2011)
• ISSN：1520-4804

文摘

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鈥揳ctivity 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.