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

Susana Conde-Ceide; Carlos M Martínez-Viturro; Jesús Alcázar; 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; José Manuel Bartolomé-Nebreda; Craig W Lindsley

doi:10.1021/acsmedchemlett.5b00181

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. eCollection 2015 Jun 11.

Authors

Susana Conde-Ceide¹, Carlos M Martínez-Viturro¹, Jesús Alcázar¹, Pedro M Garcia-Barrantes², Hilde Lavreysen³, Claire Mackie³, Paige N Vinson⁴, Jerri M Rook⁴, Thomas M Bridges⁴, J Scott Daniels⁴, Anton Megens³, Xavier Langlois³, Wilhelmus H Drinkenburg³, Abdellah Ahnaou³, Colleen M Niswender⁴, Carrie K Jones⁴, Gregor J Macdonald³, Thomas Steckler³, P Jeffrey Conn⁴, Shaun R Stauffer⁴, José Manuel Bartolomé-Nebreda¹, Craig W Lindsley⁴

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.

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.

Abstract

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