Development of a Highly Potent, Novel M5 Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)be

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• 作者：Patrick R. Gentry ; Masaya Kokubo ; Thomas M. Bridges ; Meredith J. Noetzel ; Hyekyung P. Cho ; Atin Lamsal ; Emery Smith ; Peter Chase ; Peter S. Hodder ; Colleen M. Niswender ; J. Scott Daniels ; P. Jeffrey Conn ; Craig W. Lindsley ; Michael R. Wood
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 25, 2014
• 年：2014
• 卷：57
• 期：18
• 页码：7804-7810
• 全文大小：293K
• ISSN：1520-4804

文摘

A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M₅). Application of rapid analog, iterative parallel synthesis efficiently optimized M₅ potency to arrive at the most potent M₅ PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M₅ EC₅₀ = 190 nM, rat M₅ EC₅₀ = 610 nM, brain to plasma ratio (K_p) of 0.36).