Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt.
Bioorg Med Chem
; 15(6): 2441-52, 2007 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-17258463
ABSTRACT
Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Piridinas
/
Inibidores de Proteínas Quinases
/
Inibidores Enzimáticos
/
Proteínas Proto-Oncogênicas c-akt
Limite:
Humans
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article