Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2021 Apr 1;37:127838. doi: 10.1016/j.bmcl.2021.127838. Epub 2021 Feb 5.
A high throughput screen (HTS) identified a novel, but weak (EC = 6.2 μM, 97% Glu Max) mGlu PAM chemotype based on a 1,4-thiazepane core, VU0544412. Reaction development and chemical optimization delivered a potent mGlu PAM VU6022296 (EC = 32.8 nM, 108% Glu Max) with good CNS penetration (K = 0.45, K = 0.70) and enantiopreference. Finally, VU6022296 displayed robust, dose-dependent efficacy in reversing Haloperidol-Induced Catalepsy (HIC), a rodent preclinical Parkinson's disease model.
高通量筛选（HTS）发现了一种新型但较弱的（EC=6.2 μM，Glu 最大 97%）基于 1,4-噻唑烷核心的 mGlu PAM 化学型，VU0544412。反应开发和化学优化提供了一种有效的 mGlu PAM VU6022296（EC=32.8 nM，Glu 最大 108%），具有良好的中枢神经系统穿透性（K=0.45，K=0.70）和对映体选择性。最后，VU6022296 在逆转氟哌啶醇诱导的僵住（HIC）方面表现出强大的、剂量依赖性的疗效，HIC 是一种啮齿动物临床前帕金森病模型。
