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ACS Med Chem Lett. 2015 May 20;6(6):716-20. doi: 10.1021/acsmedchemlett.5b00181. eCollection 2015 Jun 11.

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

Author information

1
Neuroscience Medicinal Chemistry and Discovery Sciences Lead Discovery, Janssen Research and Development , Jarama 75A, 45007 Toledo, Spain.
2
Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
3
Neuroscience and Discovery Sciences ADME/Tox, Janssen Research and Development , Turnhoutseweg 30, B-2340 Beerse, Belgium.
4
Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States ; Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.

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.

KEYWORDS:

4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine; JNJ-46778212; Positive allosteric modulator (PAM); VU0409551; metabotropic glutamate receptor 5 (mGlu5); schizophrenia

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