二氢噻唑并吡啶衍生物作为代谢型谷氨酸 5 型受体的新型正变构调节剂家族。
Dihydrothiazolopyridone derivatives as a novel family of positive allosteric modulators of the metabotropic glutamate 5 (mGlu5) receptor.
机构信息
Neuroscience Medicinal Chemistry, ¶CREATe Analytical Sciences, and ‡CREATe Molecular Informatics, Janssen Research and Development , Jarama 75, 45007 Toledo, Spain.
出版信息
J Med Chem. 2013 Sep 26;56(18):7243-59. doi: 10.1021/jm400650w. Epub 2013 Sep 4.
Abstract
Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.
摘要
从一个单体色满酮高通量筛选（HTS）命中物开始，我们描述了一个集中的药物化学优化工作，导致了一系列新型的苯氧甲基-二氢噻唑并吡啶酮衍生物的鉴定，这些衍生物是代谢型谷氨酸 5（mGlu5）受体的选择性正变构调节剂（PAMs）。这些二氢噻唑并吡啶酮在重组系统中增强了受体的反应。体外和体内药物代谢和药代动力学（DMPK）评估使我们能够选择化合物 16a 进行可能的抗精神病活性的临床前动物筛选评估。16a 能够以剂量依赖的方式逆转安非他命诱导的大鼠过度活跃，而在可比剂量下没有显示出任何明显的运动障碍或明显的神经副作用。描述了我们的药物化学计划的演变、构效关系（SAR 和 SPR）分析以及优化的 mGlu5 受体 PAM 16a 的详细概况。
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