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Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2017-09-20 , DOI: 10.1016/j.bmcl.2017.09.042 Andrew S Felts 1 , Alice L Rodriguez 1 , Ryan D Morrison 1 , Katrina A Bollinger 1 , Daryl F Venable 1 , Anna L Blobaum 1 , Frank W Byers 1 , Analisa Thompson Gray 1 , J Scott Daniels 1 , Colleen M Niswender 2 , Carrie K Jones 1 , P Jeffrey Conn 1 , Craig W Lindsley 3 , Kyle A Emmitte 3
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2017-09-20 , DOI: 10.1016/j.bmcl.2017.09.042 Andrew S Felts 1 , Alice L Rodriguez 1 , Ryan D Morrison 1 , Katrina A Bollinger 1 , Daryl F Venable 1 , Anna L Blobaum 1 , Frank W Byers 1 , Analisa Thompson Gray 1 , J Scott Daniels 1 , Colleen M Niswender 2 , Carrie K Jones 1 , P Jeffrey Conn 1 , Craig W Lindsley 3 , Kyle A Emmitte 3
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Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu5 NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu5 NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu5 versus DAT.
中文翻译：
发现咪唑并[1,2-a]-，[1,2,4]三唑[4,3-a]-和[1,2,4]三唑[1,5-a]吡啶-8-甲酰胺代谢型谷氨酸受体亚型5的负变构调节剂。
基于一个假设，在我们的吡啶甲酰胺mGlu5 NAM的先导序列中存在分子内氢键，我们认为可以通过引入稠合的杂环核心来修饰无活性烟酰胺系列，以产生有效的mGlu5 NAM。在这封信中，我们描述了证明该方法可行的化合物的合成和评估。在各种体外试验中分析了选定的类似物，并在大鼠药代动力学研究和强迫症小鼠模型中评估了两种化合物。辅助药理学筛选显示该系列成员对多巴胺转运蛋白（DAT）表现出中等抑制作用，并且开发了SAR，扩大了mGlu5对DAT的选择性。
更新日期：2017-09-20
中文翻译：
发现咪唑并[1,2-a]-，[1,2,4]三唑[4,3-a]-和[1,2,4]三唑[1,5-a]吡啶-8-甲酰胺代谢型谷氨酸受体亚型5的负变构调节剂。
基于一个假设，在我们的吡啶甲酰胺mGlu5 NAM的先导序列中存在分子内氢键，我们认为可以通过引入稠合的杂环核心来修饰无活性烟酰胺系列，以产生有效的mGlu5 NAM。在这封信中，我们描述了证明该方法可行的化合物的合成和评估。在各种体外试验中分析了选定的类似物，并在大鼠药代动力学研究和强迫症小鼠模型中评估了两种化合物。辅助药理学筛选显示该系列成员对多巴胺转运蛋白（DAT）表现出中等抑制作用，并且开发了SAR，扩大了mGlu5对DAT的选择性。
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