Discovery of Novel 2-((Pyridin-3-yloxy)methyl)piperazines as 伪7 Nicotinic Acetylcholine Receptor Modulators for the Treatment of Inflammatory Disorders

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• 作者：Roger B. Clark ; Diana Lamppu ; Lyn Libertine ; Amy McDonough ; Anjali Kumar ; Greg LaRosa ; Roger Rush ; Daniel Elbaum
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：3966-3983
• 全文大小：493K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

Herein we report the design, synthesis, and structure鈥揳ctivity relationships for a new class of 伪7 nicotinic acetylcholine receptor (nAChR) modulators based on the 2-((pyridin-3-yloxy)methyl)piperazine scaffold. The oxazolo[4,5-b]pyridine, (R)-18, and 4-methoxyphenylurea, (R)-47, were identified as potent and selective modulators of the 伪7 nAChR with favorable in vitro safety profiles and good oral bioavailability in mouse. Both compounds were shown to significantly inhibit cellular infiltration in a murine model of allergic lung inflammation. Despite the structural and in vivo functional similarities in the compounds, only (R)-18 was shown to be an agonist. Compound (R)-47 demonstrated silent agonist activity. These data support the hypothesis that the anti-inflammatory activity of the 伪7 nAChR is mediated by a signal transduction pathway that is independent of ion current.