N-Alkylpyrido[1‿2‿1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu_1/5 with CNS exposure in rodents

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• 作者：Andrew S. Felts^a ; ^b ; Alice L. Rodriguez^a ; ^b ; Ryan D. Morrison^a ; ^b ; Daryl F. Venable^a ; ^b ; Anna L. Blobaum^a ; ^b ; Frank W. Byers^a ; ^b ; J. Scott Daniels^a ; ^b ; Colleen M. Niswender^a ; ^b ; Carrie K. Jones^a ; ^b ; P. Jeffrey Conn^a ; ^b ; Craig W. Lindsley^a ; ^b ; ^c ; Kyle A. Emmitte^a ; ^b ; ^c ; ^{kyle.emmitte@unthsc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Metabotropic glutamate receptor subtype 1 (mGlu1) ; Metabotropic glutamate receptor subtype 5 (mGlu5) ; Negative allosteric modulator (NAM) ; Central nervous system (CNS) ; G-protein coupled receptor (GPCR)
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 April 2016
• 年：2016
• 卷：26
• 期：8
• 页码：1894-1900
• 全文大小：788 K

文摘

Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu₁ and mGlu₅) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu_1/5 NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents.