1.
Bioorg Med Chem Lett
; 21(11): 3452-6, 2011 Jun 01.
Artigo
em Inglês
| MEDLINE
| ID: mdl-21515047
RESUMO
Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.
Assuntos
Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Ratos
2.
J Med Chem
; 54(7): 2255-65, 2011 Apr 14.
Artigo
em Inglês
| MEDLINE
| ID: mdl-21375264
RESUMO
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.