Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu₁

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• 作者：Jason T. Manka ; Alice L. Rodriguez ; Ryan D. Morrison ; Daryl F. Venable ; Hyekyung P. Cho ; Anna L. Blobaum ; J. Scott Daniels ; Colleen M. Niswender ; P. Jeffrey Conn ; Craig W. Lindsley ; Kyle A. Emmitte
• 关键词：Glutamate ; GPCR ; mGlu1 ; Allosteric modulator ; CNS ; Octahydropyrrolo[3 ; 4-c]pyrrole
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 September, 2013
• 年：2013
• 卷：23
• 期：18
• 页码：5091-5096
• 全文大小：797 K

文摘

Development of SAR in an octahydropyrrolo[3,4-c]pyrrole series of negative allosteric modulators of mGlu₁ using a functional cell-based assay is described in this Letter. The octahydropyrrolo[3,4-c]pyrrole scaffold was chosen as an isosteric replacement for the piperazine ring found in the initial hit compound. Characterization of selected compounds in protein binding assays was used to identify the most promising analogs, which were then profiled in P450 inhibition assays in order to further assess the potential for drug-likeness within this series of compounds.