Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
Pharmaceutical Biology, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
J Med Chem. 2020 Nov 25;63(22):13595-13617. doi: 10.1021/acs.jmedchem.0c00620. Epub 2020 Nov 9.
The mechanistic target of rapamycin (mTOR) pathway is hyperactivated in cancer and neurological disorders. Rapalogs and mTOR kinase inhibitors (TORKi) have recently been applied to alleviate epileptic seizures in tuberous sclerosis complex (TSC). Herein, we describe a pharmacophore exploration to identify a highly potent, selective, brain penetrant TORKi. An extensive investigation of the morpholine ring engaging the mTOR solvent exposed region led to the discovery of PQR626 (). displayed excellent brain penetration and was well-tolerated in mice. In mice with a conditionally inactivated gene in glia, significantly reduced the loss of -induced mortality at 50 mg/kg p.o. twice a day. overcomes the metabolic liabilities of PQR620 (), the first-in-class brain penetrant TORKi showing efficacy in a TSC mouse model. The improved stability in human hepatocytes, excellent brain penetration, and efficacy in CKO mice qualify as a potential therapeutic candidate for the treatment of neurological disorders.
雷帕霉素（mTOR）途径的机械靶点在癌症和神经紊乱中被过度激活。雷帕霉素靶蛋白激酶抑制剂（TORKi）最近已被应用于减轻结节性硬化症（TSC）中的癫痫发作。在此，我们描述了一种药效团探索，以鉴定一种高活性、选择性、可穿透大脑的 TORKi。对与 mTOR 溶剂暴露区域结合的吗啉环进行了广泛的研究，导致了 PQR626（）的发现。 显示出优异的大脑穿透性，并且在小鼠中耐受性良好。在条件性敲除胶质细胞中的 基因的小鼠中， 以 50mg/kg po 每天两次的剂量显著降低了 -诱导的死亡率。 克服了 PQR620（）的代谢缺陷，PQR620（）是第一个穿透大脑的 TORKi，在 TSC 小鼠模型中显示出疗效。在人肝细胞中的稳定性提高、优异的大脑穿透性以及在 CKO 小鼠中的疗效使 成为治疗神经紊乱的潜在治疗候选物。
