Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4.
Bioorg Med Chem Lett
; 25(16): 3203-7, 2015 Aug 15.
Article
in En
| MEDLINE
| ID: mdl-26115573
ABSTRACT
IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity. Additionally, it was found that the pyrimidine core could be replaced with a pyridine and still retain potency and kinase selectivity. The optimization efforts led to compound 26 which had an IRAK4 IC50 of 0.7 nM, an IC50 of 55 nM on THP-1 cells stimulated with LPS, a TLR4 agonist, and greater than 100-fold selectivity versus 96% of a panel of 306 kinases.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrimidines
/
Enzyme Inhibitors
/
Interleukin-1 Receptor-Associated Kinases
Type of study:
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2015
Document type:
Article