Discovery of the First M5-Selective and CNS Penetrant Negative Allosteric Modulator (NAM) of a Muscarinic Acetylcholine Receptor: (S)-9b-(4-Chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-

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• 作者：Patrick R. Gentry ; Masaya Kokubo ; Thomas M. Bridges ; Nathan R. Kett ; Joel M. Harp ; Hyekyung P. Cho ; Emery Smith ; Peter Chase ; Peter S. Hodder ; Colleen M. Niswender ; J. Scott Daniels ; P. Jeffrey Conn ; Michael R. Wood ; Craig W. Lindsley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：9351-9355
• 全文大小：279K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M₅ subtype. ML375 is a highly selective M₅ NAM with submicromolar potency (human M₅ IC₅₀ = 300 nM, rat M₅ IC₅₀ = 790 nM, M_{1鈥?/sub>M4 IC50 > 30 渭M), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.}