Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu5)

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• 作者：Mark Turlington ; Chrysa Malosh ; Jon Jacobs ; Jason T. Manka ; Meredith J. Noetzel ; Paige N. Vinson ; Satyawan Jadhav ; Elizabeth J. Herman ; Hilde Lavreysen ; Claire Mackie ; Jos茅 M. Bartolom茅-Nebreda ; Susana Conde-Ceide ; M. Luz Mart铆n-Mart铆n ; Han Min Tong ; Silvia L贸pez ; Gregor J. MacDonald ; Thomas Steckler ; J. Scott Daniels ; C. David Weaver ; Colleen M. Niswender ; Carrie K. Jones ; P. Jeffrey Conn ; Craig W. Lindsley ; Shaun R. Stauffer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 10, 2014
• 年：2014
• 卷：57
• 期：13
• 页码：5620-5637
• 全文大小：779K
• ISSN：1520-4804

文摘

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu₅) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu₅ PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu₅ as well as antagonist activity at mGlu₃. Structure鈥揳ctivity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu₅ PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.