Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia

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• 作者：Susana Conde-Ceide ; Carlos M. Mart铆nez-Viturro ; Jes煤s Alc谩zar ; Pedro M. Garcia-Barrantes ; Hilde Lavreysen ; Claire Mackie ; Paige N. Vinson ; Jerri M. Rook ; Thomas M. Bridges ; J. Scott Daniels ; Anton Megens ; Xavier Langlois ; Wilhelmus H. Drinkenburg ; Abdellah Ahnaou ; Colleen M. Niswender ; Carrie K. Jones ; Gregor J. Macdonald ; Thomas Steckler ; P. Jeffrey Conn ; Shaun R. Stauffer ; Jos茅 Manuel Bartolom茅-Nebreda ; Craig W. Lindsley
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：June 11, 2015
• 年：2015
• 卷：6
• 期：6
• 页码：716-720
• 全文大小：343K
• ISSN：1948-5875

文摘

Herein, we report the structure鈥揳ctivity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu₅) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.