Development of novel M₁ antagonist scaffolds through the continued optimization of the MLPCN probe ML012

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• 作者：Bruce J. Melancon ; Thomas J. Utley ; Christian Sevel ; Margrith E. Mattmann ; Yiu-Yin Cheung ; Thomas M. Bridges ; Ryan D. Morrison ; Douglas J. Sheffler ; Colleen M. Niswender ; J. Scott Daniels ; P. Jeffrey Conn ; Craig W. Lindsley ; Michael R. Wood
• 关键词：Muscarinic acetylcholine receptor 1 ; M1 antagonist ; ML012 ; VU0455691 ; VU0452865
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 August, 2012
• 年：2012
• 卷：22
• 期：15
• 页码：5035-5040
• 全文大小：4160 K

文摘

This Paper describes the continued optimization of an MLPCN probe molecule M₁ antagonist (ML012) through an iterative parallel synthesis approach. After several rounds of modifications of the parent compound, we arrived at a new azetidine scaffold that displayed improved potency while maintaining a desirable level of selectivity over other muscarinic receptor subtypes. Data for representative molecules 7w (VU0452865) and 12a (VU0455691) are presented.