4-(Difluoromethyl)-5-(4-((3,5)-3,5-dimethylmorpholino)-6-(()-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 (). 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.