X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase.
Bioorg Med Chem Lett
; 22(9): 3296-300, 2012 May 01.
Article
en En
| MEDLINE
| ID: mdl-22464456
ABSTRACT
Beginning with a screening hit, unique thienopyrazole-indole inhibitors of Itk (interleukin-2-inducible tyrosine kinase) were designed, synthesized, and crystallized in the target kinase. Although initial compounds were highly active in Itk, they were not selective. Increasing the steric bulk around a tertiary alcohol at the 5-indole position dramatically improved selectivity toward Lyk and Syk, but not Txk. Substitutions at the 3- and 4-indole positions gave less active compounds that remained poorly selective. A difluoromethyl substitution at the 5-position of the thienopyrazole led to a highly potent and selective compound. Phenyl at this position reduced activity and selectivity while pushing the side-chains of Lys-391 and Asp-500 away from the binding pocket. Novel and selective thienopyrazole inhibitors of Itk were designed as a result of combining structure-based design and medicinal chemistry.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Proteínas Tirosina Quinasas
/
Diseño de Fármacos
/
Inhibidores de Proteínas Quinasas
Límite:
Humans
Idioma:
En
Año:
2012
Tipo del documento:
Article