Discovery of potent and selective reversible Bruton's tyrosine kinase inhibitors.
Bioorg Med Chem
; 40: 116163, 2021 06 15.
Article
em En
| MEDLINE
| ID: mdl-33932711
ABSTRACT
Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose the discovery of a novel imidazo[4,5-b]pyridine series of potent, selective reversible BTK inhibitors through a rational design approach. From a starting hit molecule 1, medicinal chemistry optimization led to the development of a lead compound 30, which exhibited 58 nM BTK inhibitory potency in human whole blood and high kinome selectivity. Additionally, the compound demonstrated favorable pharmacokinetics (PK), and showed potent dose-dependent efficacy in a rat CIA model.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Piridinas
/
Inibidores de Proteínas Quinases
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Descoberta de Drogas
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Tirosina Quinase da Agamaglobulinemia
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Imidazóis
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2021
Tipo de documento:
Article