新型咪唑并嘧啶酮和二氢咪唑并嘧啶酮系列作为代谢型谷氨酸受体5（mGlu5）的正变构调节剂的发现与构效关系研究
Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).
作者信息
Martín-Martín María Luz, Bartolomé-Nebreda José Manuel, Conde-Ceide Susana, Alonso de Diego Sergio A, López Silvia, Martínez-Viturro Carlos M, Tong Han Min, Lavreysen Hilde, Macdonald Gregor J, Steckler Thomas, Mackie Claire, Bridges Thomas M, Daniels J Scott, Niswender Colleen M, Noetzel Meredith J, Jones Carrie K, Conn P Jeffrey, Lindsley Craig W, Stauffer Shaun R
机构信息
Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama 75A, 45007 Toledo, Spain.
出版信息
Bioorg Med Chem Lett. 2015 Mar 15;25(6):1310-7. doi: 10.1016/j.bmcl.2015.01.038. Epub 2015 Jan 28.
Abstract
We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
摘要
我们报告了两个新型咪唑并嘧啶酮和二氢咪唑并嘧啶酮系列作为代谢型谷氨酸受体5（mGlu5）正向变构调节剂（PAM）的发现及构效关系研究。对咪唑并嘧啶酮核心结构西部和东部的几个结构特征及其组合进行探索，发现化合物4a作为一种mGlu5 PAM，具有良好的体外效力和功效、可接受的药物代谢及药代动力学（DMPK）性质，并且在基于苯丙胺的精神病模型中具有体内疗效。然而，临床前物种中存在中枢神经系统介导的不良反应，妨碍了进一步的体内评估。
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2
Metabotropic glutamate receptor 5-positive allosteric modulators for the treatment of schizophrenia (2004-2012).
Pharm Pat Anal. 2013 Jan;2(1):93-108. doi: 10.4155/ppa.12.82.
3
Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254).
J Med Chem. 2013 Oct 24;56(20):7976-96. doi: 10.1021/jm401028t. Epub 2013 Oct 9.
4
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5
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Drug Metab Dispos. 2013 Sep;41(9):1703-14. doi: 10.1124/dmd.113.052084. Epub 2013 Jul 2.
6
Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity.
Biol Psychiatry. 2013 Mar 15;73(6):501-9. doi: 10.1016/j.biopsych.2012.09.012. Epub 2012 Nov 7.
7
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8
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9
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10
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