Purine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors for autoimmune diseases.
Bioorg Med Chem Lett
; 24(9): 2206-11, 2014 May 01.
Article
em En
| MEDLINE
| ID: mdl-24685542
ABSTRACT
Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Purinas
/
Proteínas Tirosina Quinases
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Inibidores de Proteínas Quinases
Limite:
Animals
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Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Ano de publicação:
2014
Tipo de documento:
Article