RESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular , Ensaios de Triagem em Larga Escala , Humanos , Lipopolissacarídeos/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato , Receptor 4 Toll-Like/antagonistas & inibidoresRESUMO
Interleukin receptor-associated kinase 4 (IRAK4) is a critical element of the Toll-like/interleukin-1 receptor inflammation signaling pathway. A screening campaign identified a novel diaminopyrimidine hit that exhibits weak IRAK4 inhibitory activity and a ligand efficiency of 0.25. Hit-to-lead activities were conducted through independent SAR studies of each of the four pyrimidine substituents. Optimal activity was observed upon removal of the pyrimidine C-4 chloro substituent. The intact C-6 carboribose is required for IRAK4 inhibition. Numerous heteroaryls were tolerated at the C-5 position, with azabenzothiazoles conferring the best activities. Aminoheteroaryls were preferred at the C-2 position. These studies led to the discovery of inhibitors 35, 36, and 38 that exhibit nanomolar inhibition of IRAK4, improved ligand efficiencies, and modest kinase selectivities.