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

Abstract	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.
Authors	Chiara Borsari, Erhan Keles, Denise Rageot, Andrea Treyer, Thomas Bohnacker, Lukas Bissegger, Martina De Pascale, Anna Melone, Rohitha Sriramaratnam, Florent Beaufils, Matthias Hamburger, Paul Hebeisen, Wolfgang Löscher, Doriano Fabbro, Petra Hillmann, Matthias P Wymann
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 22 Pg. 13595-13617 (11 25 2020) ISSN: 1520-4804 [Electronic] United States
PMID	33166139 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Morpholines MTOR protein, human TOR Serine-Threonine Kinases
Topics	Administration, Oral Animals Brain (drug effects, metabolism) Dogs Female Hepatocytes (drug effects, metabolism) Humans Madin Darby Canine Kidney Cells Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice, Nude Morpholines (administration & dosage, chemistry, metabolism) Nervous System Diseases (drug therapy, metabolism) Rats Rats, Sprague-Dawley TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!