Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Acute Neurology Research Unit, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
J Med Chem. 2021 Oct 28;64(20):15402-15419. doi: 10.1021/acs.jmedchem.1c01458. Epub 2021 Oct 15.
Apoptosis signal-regulating kinase 1 (ASK1) is one of the key mediators of the cellular stress response that regulates inflammation and apoptosis. To probe the therapeutic value of modulating this pathway in preclinical models of neurological disease, we further optimized the profile of our previously reported inhibitor . This effort led to the discovery of , a potent (cell IC = 25 nM) and selective ASK1 inhibitor with suitable pharmacokinetic and brain penetration (rat Cl/Cl = 1.6/56 L/h/kg and = 0.46) for proof-of-pharmacology studies. Specifically, the ability of to inhibit ASK1 in the central nervous system (CNS) was evaluated in a human tau transgenic (Tg4510) mouse model exhibiting elevated brain inflammation. In this study, transgenic animals treated with (at 3, 10, and 30 mg/kg, BID/PO for 4 days) showed a robust reduction of inflammatory markers (, IL-1β) in the cortex, thus confirming inhibition of ASK1 in the CNS.
凋亡信号调节激酶 1（ASK1）是细胞应激反应的关键介质之一，可调节炎症和细胞凋亡。为了探究在神经疾病的临床前模型中调节该途径的治疗价值，我们进一步优化了之前报道的抑制剂的特性。这一努力导致了发现，一种有效的（细胞 IC = 25 nM）和选择性的 ASK1 抑制剂，具有合适的药代动力学和脑穿透性（大鼠 Cl/Cl = 1.6/56 L/h/kg 和 = 0.46），可用于药理学研究。具体而言，在表现出脑内炎症升高的人类 tau 转基因（Tg4510）小鼠模型中评估了化合物在中枢神经系统（CNS）中抑制 ASK1 的能力。在这项研究中，用化合物（3、10 和 30 mg/kg，BID/PO，连续 4 天）处理的转基因动物，大脑皮层中的炎症标志物（、IL-1β）显著减少，从而证实了在 CNS 中抑制 ASK1。
