VU0409551/JNJ-46778212的发现：一种靶向精神分裂症的mGlu5正变构调节剂临床候选药物。
Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.
作者信息
Conde-Ceide Susana, Martínez-Viturro Carlos M, Alcázar Jesús, 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, Bartolomé-Nebreda José Manuel, Lindsley Craig W
机构信息
Neuroscience Medicinal Chemistry and Discovery Sciences Lead Discovery, Janssen Research and Development , Jarama 75A, 45007 Toledo, Spain.
Department of Pharmacology and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
出版信息
ACS Med Chem Lett. 2015 May 20;6(6):716-20. doi: 10.1021/acsmedchemlett.5b00181. eCollection 2015 Jun 11.
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.
摘要
在此，我们报告了一系列新型的(2-(苯氧基甲基)-6,7-二氢恶唑并[5,4-c]吡啶-5(4H)-基(芳基)甲酮的构效关系，这些化合物是强效、选择性且口服生物可利用的代谢型谷氨酸受体亚型5（mGlu5）正变构调节剂（PAMs）。基于其在精神分裂症多个领域的多种临床前模型中强大的体外效力和体内疗效，再加上良好的药物代谢动力学特性和可接受的治疗窗口，17a（VU0409551/JNJ-46778212）被选为进一步开发的候选药物。
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