一种强效新型M5正变构调节剂（PAM）的研发，该调节剂具有中枢神经系统暴露活性：1-((1H-吲唑-5-基)磺酰基)-N-乙基-N-(2-(三氟甲基)苄基)哌啶-4-甲酰胺（ML380）。
Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380).
作者信息
Gentry Patrick R, Kokubo Masaya, Bridges Thomas M, Noetzel Meredith J, Cho Hyekyung P, Lamsal Atin, Smith Emery, Chase Peter, Hodder Peter S, Niswender Colleen M, Daniels J Scott, Conn P Jeffrey, Lindsley Craig W, Wood Michael R
机构信息
Department of Pharmacology, ‡Vanderbilt Center for Neuroscience Drug Discovery, and §Vanderbilt Specialized Chemistry Center for Accelerated Probe Development (MLPCN), Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
出版信息
J Med Chem. 2014 Sep 25;57(18):7804-10. doi: 10.1021/jm500995y. Epub 2014 Sep 3.
A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5 potency to arrive at the most potent M5 PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5 EC50 = 190 nM, rat M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).
一项功能性高通量筛选确定了一种用于毒蕈碱型乙酰胆碱受体（mAChR）亚型5（M5）正变构调节（PAM）的新型化学类型。快速类似物迭代平行合成的应用有效地优化了M5的效力，得到了迄今为止制备的最有效的M5 PAM，并提供了工具化合物8n（ML380），其显示出适度的中枢神经系统渗透性（人M5 EC50 = 190 nM，大鼠M5 EC50 = 610 nM，脑血浆比（Kp）为0.36）。
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