Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
ACS Chem Neurosci. 2021 Dec 15;12(24):4524-4534. doi: 10.1021/acschemneuro.1c00557. Epub 2021 Dec 2.
The detailed pharmacology and therapeutic potential of the central PAR4 receptors are poorly understood due to a lack of potent, selective, and brain-penetrant tool compounds. Despite this, robust data with biochemical and genetic tools show the therapeutic potential of PAR4 antagonists in traumatic brain injury, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders with a neuroinflammatory component. Thus, we performed a functional HTS campaign, identified a fundamentally new PAR4 competitive inhibitor chemotype, optimized this new series (increased potency >45-fold), discovered enantiospecific activity (though opposing preference for human versus mouse PAR4), and engendered high central nervous system penetration (rat 's of 0.52 to 4.2 and 's of 0.52 to 1.2).
由于缺乏强效、选择性和穿透脑屏障的工具化合物，中枢 PAR4 受体的详细药理学和治疗潜力仍未被充分了解。尽管如此，具有生化和遗传工具的强有力数据表明，PAR4 拮抗剂在创伤性脑损伤、阿尔茨海默病、帕金森病和其他具有神经炎症成分的神经退行性疾病中的治疗潜力。因此，我们进行了一项功能性高通量筛选（HTS）活动，鉴定出一种全新的 PAR4 竞争性抑制剂化学型，对该新系列进行了优化（效力提高了 45 倍以上），发现了对映体特异性活性（尽管对人源和鼠源 PAR4 的偏好相反），并产生了较高的中枢神经系统穿透性（大鼠为 0.52 至 4.2，小鼠为 0.52 至 1.2）。
