2. Academic Validation
  3. 4-(Difluoromethyl)-5-(4-((3 R,5 S)-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

4-(Difluoromethyl)-5-(4-((3 R,5 S)-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

  • J Med Chem. 2020 Nov 25;63(22):13595-13617. doi: 10.1021/acs.jmedchem.0c00620.
Chiara Borsari 1,  Erhan Keles 1,  Denise Rageot 1,  Andrea Treyer 2,  Thomas Bohnacker 1,  Lukas Bissegger 1,  Martina De Pascale 1,  Anna Melone 1,  Rohitha Sriramaratnam 1,  Florent Beaufils 3,  Matthias Hamburger 2,  Paul Hebeisen 3,  Wolfgang Löscher 4 5,  Doriano Fabbro 3,  Petra Hillmann 3,  Matthias P Wymann 1
Affiliations

Affiliations

  • 1 Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
  • 2 Pharmaceutical Biology, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
  • 3 PIQUR Therapeutics AG, Hochbergerstrasse 60, 4057 Basel, Switzerland.
  • 4 Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, 30559 Hannover, Germany.
  • 5 Center for Systems Neuroscience, University of Veterinary Medicine, 30559 Hannover, Germany.
PMID: 33166139 DOI: 10.1021/acs.jmedchem.0c00620
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.

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