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
de 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.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Purines
/
Protein-tyrosine kinases
/
Inhibiteurs de protéines kinases
Limites:
Animals
/
Humans
Langue:
En
Journal:
Bioorg Med Chem Lett
Sujet du journal:
BIOQUIMICA
/
QUIMICA
Année:
2014
Type de document:
Article