4‑(Difluoromethyl)-5-(4-((3<i>R</i>,5<i>S</i>)‑3,5-dimethylmorpholino)-6-((<i>R</i>)‑3-methylmorpholino)-1,3,5-triazin-2-yl)pyridin-2-amine (PQR626), a Potent, Orally Available, and Brain-Penetrant mTOR Inhibitor for the Treatment of Neurological Disorders

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 (8). 8 displayed excellent brain penetration and was well-tolerated in mice. In mice with a conditionally inactivated Tsc1 gene in glia, 8 significantly reduced the loss of Tsc1-induced mortality at 50 mg/kg p.o. twice a day. 8 overcomes the metabolic liabilities of PQR620 (52), 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 Tsc1GFAPCKO mice qualify 8 as a potential therapeutic candidate for the treatment of neurological disorders.雷帕霉素靶蛋白（mechanistic target of rapamycin, mTOR）通路在癌症与神经系统疾病中呈过度激活状态。雷帕霉素类似物（rapalogs）与mTOR激酶抑制剂（TORKi）近年来被应用于缓解结节性硬化症（tuberous sclerosis complex, TSC）患者的癫痫发作。本文中，我们通过药效团探索研究，旨在筛选出高效、高选择性且可透过血脑屏障的TORKi。针对结合mTOR溶剂暴露区域的吗啉环开展了系统性研究，最终发现了化合物PQR626（即化合物8）。该化合物展现出优异的血脑屏障穿透性，且在小鼠体内耐受性良好。在胶质细胞中Tsc1基因条件性敲除的小鼠模型中，以50mg/kg剂量每日两次口服给药时，化合物8可显著降低Tsc1缺失诱导的小鼠死亡率。相较于首款可透过血脑屏障、且在TSC小鼠模型中展现药效的首创级脑穿透性TORKi PQR620（即化合物52），化合物8克服了其代谢缺陷。人肝细胞中稳定性提升、优异的血脑屏障穿透性以及在Tsc1GFAPCKO小鼠模型中的药效，使化合物8有望成为治疗神经系统疾病的潜在候选药物。