Pyrazoloheteroaryls: novel p38alpha MAP kinase inhibiting scaffolds with oral activity.

A test library with three novel p38alpha inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38alpha inhibitors, for example, pyrazolo[3,4-b]pyridine 9, pyrazolo[3,4-d]pyrimidine 18a and pyrazolo[3,4-b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.

SAR of benzoylpyridines and benzophenones as p38alpha MAP kinase inhibitors with oral activity.

Benzoylpyridines and benzophenones were synthesized and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Oral activity was found to depend upon substitution: 1,1-dimethylpropynylamine substituted benzophenone 10b (IC50: 14 nM) and pyridinoyl substituted benzimidazole 17b (IC50: 21 nM) showed highest efficacy and selectivity with ED50s of 9.5 and 8.

Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis.

A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2-b]pyridines was prepared and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.