1,2,3,4-Tetrahydroquinoline-Based Selective Human Neuronal Nitric Oxide Synthase (nNOS) Inhibitors: Lead Optimization Studies Resulting in the Identification of N-(1-(2-(Methylamino)ethyl)-1,2,

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• 作者：Jailall Ramnauth ; Paul Renton ; Peter Dove ; Subhash C. Annedi ; Joanne Speed ; Sarah Silverman ; Gabriela Mladenova ; Shawn P. Maddaford ; Salvatore Zinghini ; Suman Rakhit ; John Andrews ; David K. H. Lee ; Dongqin Zhang ; Frank Porreca
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 22, 2012
• 年：2012
• 卷：55
• 期：6
• 页码：2882-2893
• 全文大小：380K
• 年卷期：v.55,no.6(March 22, 2012)
• ISSN：1520-4804

文摘

Numerous studies have shown that selective nNOS inhibitors could be therapeutic in many neurological disorders. Previously, we reported a series of 1,2,3,4-tetrahydroquinoline-based potent and selective nNOS inhibitors, highlighted by 1 ( J. Med. Chem. 2011, 54, 5562鈭?575). Despite showing activity in two rodent pain models, 1 suffered from low oral bioavailability (18%) and moderate hERG channel inhibition (IC₅₀ = 4.7 渭M). To optimize the properties of 1, we synthesized a small focused library containing various alkylamino groups on the 1-position of the 1,2,3,4-tetrahydroquinoline scaffold. The compounds were triaged based on their activity in the NOS and hERG manual patch clamp assays and their calculated physicochemical parameters. From these studies, we identified 47 as a potent and selective nNOS inhibitor with improved oral bioavailability (60%) and no hERG channel inhibition (IC₅₀ > 30 渭M). Furthermore, 47 was efficacious in the Chung model of neuropathic pain and has an excellent safety profile, making it a promising preclinical development candidate.