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

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

  • ACS Med Chem Lett. 2015 May 20;6(6):716-20. doi: 10.1021/acsmedchemlett.5b00181.
Susana Conde-Ceide 1,  Carlos M Martínez-Viturro 1,  Jesús Alcázar 1,  Pedro M Garcia-Barrantes 2,  Hilde Lavreysen 3,  Claire Mackie 3,  Paige N Vinson 4,  Jerri M Rook 4,  Thomas M Bridges 4,  J Scott Daniels 4,  Anton Megens 3,  Xavier Langlois 3,  Wilhelmus H Drinkenburg 3,  Abdellah Ahnaou 3,  Colleen M Niswender 4,  Carrie K Jones 4,  Gregor J Macdonald 3,  Thomas Steckler 3,  P Jeffrey Conn 4,  Shaun R Stauffer 4,  José Manuel Bartolomé-Nebreda 1,  Craig W Lindsley 4
Affiliations

Affiliations

  • 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.
PMID: 26157544 DOI: 10.1021/acsmedchemlett.5b00181
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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