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Chemical and Physical Biology Program

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

AUTHORS

Conde-Ceide S , Martínez-Viturro CM , Alcázar J , Garcia-Barrantes PM , Lavreysen H , Mackie C , Vinson PN , Rook JM , Bridges TM , Daniels JS , Megens A , Langlois X , Drinkenburg WH , Ahnaou A , Niswender CM , Jones CK , Macdonald GJ , Steckler T , Conn PJ , Stauffer SR , Bartolomé-Nebreda JM , Lindsley CW , . ACS medicinal chemistry letters. 2015 6 11; 6(6). 716-20

ABSTRACT

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 (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.

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 (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.