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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
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4604297
Author(s) Borsari, Chiara; Keles, Erhan; Rageot, Denise; Treyer, Andrea; Bohnacker, Thomas; Bissegger, Lukas; De Pascale, Martina; Melone, Anna; Sriramaratnam, Rohitha; Beaufils, Florent; Hamburger, Matthias; Hebeisen, Paul; Löscher, Wolfgang; Fabbro, Doriano; Hillmann, Petra; Wymann, Matthias P.
Author(s) at UniBasel Hamburger, Matthias
Treyer, Andrea
Year 2020
Title 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
Journal Journal of Medicinal Chemistry
Volume 63
Number 22
Pages / Article-Number 13595-13617
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.
Publisher American Chemical Society
ISSN/ISBN 0022-2623 ; 1520-4804
edoc-URL https://edoc.unibas.ch/79465/
Full Text on edoc No
Digital Object Identifier DOI 10.1021/acs.jmedchem.0c00620
 
   

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