Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity

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• 作者：Mark D. ChappellRenhua Li ; Stephon C. Smith ; Bruce A. Dressman ; Eric G. Tromiczak ; Allie E. Tripp ; Maria-Jesus Blanco ; Tatiana Vetman ; Steven J. Quimby ; James Matt ; Thomas C. Britton ; Adam M. Fivush ; Jeffrey M. Schkeryantz ; Daniel Mayhugh ; Jon A. Erickson ; Mark G. Bures ; Carlos Jaramillo ; Mercedes Carpintero ; José Eugenio de Diego ; Mario Barberis ; Susana Garcia-Cerrada ; José F. Soriano ; Stephen Antonysamy ; Shane Atwell ; Iain MacEwan ; Bradley Condon ; Christine Sougias ; Jing WangAiping Zhang ; Kris Conners ; Chris Groshong ; Stephen R. Wasserman ; John W. Koss ; Jeffrey M. Witkin ; Xia Li ; Carl Overshiner ; Keith A. Wafford ; Wesley Seidel ; Xu-Shan Wang ; Beverly A. Heinz ; Steven Swanson ; John T. Catlow ; David W. Bedwell ; James A. Monn ; Charles H. Mitch ; Paul L. Ornstein
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 22, 2016
• 年：2016
• 卷：59
• 期：24
• 页码：10974-10993
• 全文大小：1075K
• ISSN：1520-4804

文摘

As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu_2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu_2/3 antagonists. Exploration of this structure–activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu_2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu₂) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu₂ receptor protein. The resulting cocrystal structure revealed the specific ligand–protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu₂ antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu₂ IC₅₀ value.