Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders.
Animals
Anticonvulsants
/ metabolism
Binding Sites
Brain
/ drug effects
Drug Discovery
Humans
Male
Mice, Inbred C57BL
Mice, Knockout
Neurons
/ drug effects
Protein Binding
Protein Kinase Inhibitors
/ metabolism
Pyrimidines
/ metabolism
Rats
Seizures
/ drug therapy
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Thiazoles
/ metabolism
Tuberous Sclerosis Complex 1 Protein
/ genetics
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
13 02 2020
13 02 2020
Historique:
pubmed:
21
1
2020
medline:
4
8
2020
entrez:
21
1
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 31955578
doi: 10.1021/acs.jmedchem.9b01398
doi:
Substances chimiques
Anticonvulsants
0
Protein Kinase Inhibitors
0
Pyrimidines
0
Thiazoles
0
Tsc1 protein, mouse
0
Tuberous Sclerosis Complex 1 Protein
0
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM