Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R

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• 作者：James A. Monn ; Lourdes Prieto ; Lorena Taboada ; Junliang Hao ; Matthew R. Reinhard ; Steven S. Henry ; Christopher D. Beadle ; Lesley Walton ; Teresa Man ; Helene Rudyk ; Barry Clark ; David Tupper ; S. Richard Baker ; Carlos Lamas ; Carlos Montero ; Alicia Marcos ; Jaime Blanco ; Mark Bures ; David K. Clawson ; Shane Atwell ; Frances Lu ; Jing Wang ; Marijane Russell ; Beverly A. Heinz ; Xushan Wang ; Joan H. Carter ; Brian G. Getman ; John T. Catlow ; Steven Swanson ; Bryan G. Johnson ; David B. Shaw ; David L. McKinzie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 24, 2015
• 年：2015
• 卷：58
• 期：18
• 页码：7526-7548
• 全文大小：1151K
• ISSN：1520-4804

文摘

Identification of orthosteric mGlu_2/3 receptor agonists capable of discriminating between individual mGlu₂ and mGlu₃ subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu_2/3 subtypes, a number of high potency and efficacy mGlu₂ receptor agonists exhibiting low potency mGlu₃ partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu₂ and hmGlu₃ combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu₂ receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu₂ receptors in vivo.