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

被引：18

作者：

Borsari, Chiara ^{[1
]}

Keles, Erhan ^{[1
]}

Rageot, Denise ^{[1
]}

Treyer, Andrea ^{[2
]}

Bohnacker, Thomas ^{[1
]}

Bissegger, Lukas ^{[1
]}

De Pascale, Martina ^{[1
]}

Melone, Anna ^{[1
]}

Sriramaratnam, Rohitha ^{[1
]}

Beaufils, Florent ^{[3
]}

Hamburger, Matthias ^{[2
]}

Hebeisen, Paul ^{[3
]}

Loscher, Wolfgang ^{[4
,5
]}

Fabbro, Doriano ^{[3
]}

Hillmann, Petra ^{[3
]}

Wymann, Matthias P. ^{[1
]}

机构：

[1] Univ Basel, Dept Biomed, CH-4058 Basel, Switzerland

[2] Univ Basel, Pharmactr, Pharmaceut Biol, CH-4056 Basel, Switzerland

[3] PIQUR Therapeut AG, CH-4057 Basel, Switzerland

[4] Univ Vet Med, Dept Pharmacol Toxicol & Pharm, D-30559 Hannover, Germany

[5] Univ Vet Med, Ctr Syst Neurosci, D-30559 Hannover, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 22期

基金：

欧盟地平线“2020”; 瑞士国家科学基金会;

关键词：

D O I：

10.1021/acs.jmedchem.0c00620

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 Tsc1(GFAP )CKO mice qualify 8 as a potential therapeutic candidate for the treatment of neurological disorders.

引用

页码：13595 / 13617

页数：23

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