A hit to lead discovery of novel N-methylated imidazolo-, pyrrolo-, and pyrazolo-pyrimidines as potent and selective mTOR inhibitors.
Bioorg Med Chem Lett
; 23(18): 5097-104, 2013 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-23932790
ABSTRACT
A series of N-7-methyl-imidazolopyrimidine inhibitors of the mTOR kinase have been designed and prepared, based on the hypothesis that the N-7-methyl substituent on imidazolopyrimidine would impart selectivity for mTOR over the related PI3Kα and δ kinases. The corresponding N-Me substituted pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines also show potent mTOR inhibition with selectivity toward both PI3α and δ kinases. The most potent compound synthesized is pyrazolo[4,3-d]pyrimidine 21c. Compound 21c shows a Ki of 2 nM against mTOR inhibition, remarkable selectivity (>2900×) over PI3 kinases, and excellent potency in cell-based assays.
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MEDLINE
Assunto principal:
Pirimidinas
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Inibidores de Proteínas Quinases
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Descoberta de Drogas
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Serina-Treonina Quinases TOR
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article