Discovery and Characterization of a Novel Dihydroisoxazole Class of 伪-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Potentiators

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• 作者：Nandini C. Patel ; Jacob Schwarz ; Xinjun J. Hou ; Dennis J. Hoover ; Longfei Xie ; Anton J. Fliri ; Randall J. Gallaschun ; John T. Lazzaro ; Dianne K. Bryce ; William E. Hoffmann ; Ashley N. Hanks ; Dina McGinnis ; Eric S. Marr ; Justin L. Gazard ; Mih谩ly Haj贸s ; Renato J. Scialis ; Raymond S. Hurst ; Christopher L. Shaffer ; Jayvardhan Pandit ; Christopher J. O鈥橠onnell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：9180-9191
• 全文大小：595K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

Positive allosteric modulators (鈥減otentiators鈥? of 伪-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors. Subsequent structure-based drug design using X-ray crystal structures of the ligand-binding domain of human GluA2 led to the discovery of both PF-04725379 (11), which in tritiated form became a novel ligand for characterizing the binding affinities of subsequent AMPAR potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.