Discovery of VU0409551/JNJ-46778212: An mGlu(5) Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia

作者：Conde Ceide Susana; Martinez Viturro Carlos M; Alcazar Jesus; Garcia Barrantes Pedro M; Lavreysen Hilde; Mackie Claire; Vinson Paige N; Rook Jerri M; Bridges Thomas M; Daniels J Scott; Megens Anton; Langlois Xavier; Drinkenburg Wilhelmus H; Ahnaou Abdellah; Niswender Colleen M; Jones Carrie K; Macdonald Gregor J; Steckler Thomas; Conn P Jeffrey; Stauffer Shaun R; Manuel Bartolome Nebreda Jose; Lindsley Craig W

来源：ACS Medicinal Chemistry Letters, 2015, 6(6): 716-720.

DOI：10.1021/acsmedchemlett.5b00181

• Positive allosteric modulator (PAM)
• metabotropic glutamate receptor 5 (mGlu(5))
• 4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine
• VU0409551
• JNJ-46778212
• schizophrenia

Herein, we report the structure activity 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 (mGlu(5)) 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.

• 出版日期2015-6