Structure−Activity Relationships Comparing N-(6-Methylpyridin-yl)-Substituted Aryl Amides to 2-Methyl-6-(substituted-arylethynyl)pyridines or 2-Methyl-4-(substituted-arylethynyl)thiazoles

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• 作者：Santosh S. Kulkarni ; Mu-Fa Zou ; Jianjing Cao ; Jeffrey R. Deschamps ; Alice L. Rodriguez ; P. Jeffrey Conn ; Amy Hauck Newman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：June 11, 2009
• 年：2009
• 卷：52
• 期：11
• 页码：3563-3575
• 全文大小：308K
• 年卷期：v.52,no.11(June 11, 2009)
• ISSN：1520-4804

文摘

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in anxiety, depression, pain, mental retardation, and addiction. The potent and selective noncompetitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP, 1) has been a critically important tool used to further elucidate the role of mGluR5 in these CNS disorders. In an effort to provide novel and structurally diverse selective mGluR5 antagonists, we previously described a set of analogues with moderate activity wherein the alkyne bond was replaced with an amide group. In the present report, extended series of both amide and alkyne-based ligands were synthesized. MGluR5 binding and functional data were obtained that identified (1) several novel alkynes with comparable affinities to 1 at mGluR5 (e.g., 10 and 20–23), but (2) most structural variations to the amide template were not well tolerated, although a few potent amides were discovered (e.g., 55 and 56). Several of these novel analogues show drug-like physical properties (e.g., cLogP range = 2−5) that support their use for in vivo investigation into the role of mGluR5 in CNS disorders.