6,7-二氢吡唑并[1,5-a]吡嗪-4-酮衍生物作为新型系列mGlu5受体正向变构调节剂在精神分裂症临床前模型中的疗效的初步研究。
Preliminary investigation of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives as a novel series of mGlu5 receptor positive allosteric modulators with efficacy in preclinical models of schizophrenia.
作者信息
Conde-Ceide Susana, Alcázar Jesús, Alonso de Diego Sergio A, López Silvia, Martín-Martín María Luz, Martínez-Viturro Carlos M, Pena Miguel-Angel, Tong Han Min, Lavreysen Hilde, Mackie Claire, Bridges Thomas M, Daniels J Scott, Niswender Colleen M, Jones Carrie K, Macdonald Gregor J, Steckler Thomas, Conn P Jeffrey, Stauffer Shaun R, Lindsley Craig W, Bartolomé-Nebreda José Manuel
机构信息
Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
Neuroscience, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
出版信息
Bioorg Med Chem Lett. 2016 Jan 15;26(2):429-434. doi: 10.1016/j.bmcl.2015.11.098. Epub 2015 Nov 28.
As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.
作为我们为最近披露的代谢型谷氨酸受体5（mGlu5）正向变构调节剂（PAM）临床候选药物VU0490551/JNJ - 46778212寻找合适备用化合物的努力的一部分，本信函详细介绍了一系列新型6,7 - 二氢吡唑并[1,5 - a]吡嗪 - 4 - 酮衍生物的研究情况及挑战。通过这些研究，化合物4k成为一种强效且选择性的mGlu5 PAM，在体外（药理学和药物代谢动力学及毒性）表现出总体吸引人的特性，并且在精神分裂症临床前模型中具有体内疗效。然而，由于严重限制中枢神经系统相关副作用，该化合物的进一步研发受阻，这证实了先前报道的过度mGlu5激活与靶点相关毒性之间的关联。
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