Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders.
J Med Chem
; 63(3): 1068-1083, 2020 02 13.
Article
en En
| MEDLINE
| ID: mdl-31955578
ABSTRACT
Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an in-house purine-based compound, optimization of the physicochemical properties of a thiazolopyrimidine series led to the discovery of the small molecule 7, a potent and selective brain-penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, 7 corrected the mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene. These results demonstrate the potential utility of this tool compound to test therapeutic hypotheses that depend on mTOR hyperactivity in the CNS.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Convulsiones
/
Tiazoles
/
Inhibidores de Proteínas Quinasas
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Serina-Treonina Quinasas TOR
Límite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos