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 p38α inhibitors and in vivo in several models of rheumatoid arthritis. Four structures––32, 37, 45 and 59––were identified as potent inhibitors of p38α with high efficacy in the LPS induced TNFα release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o.