The mitogen-activated protein kinase p38a has been shown to be on the critical path to pro-inflammatory cytokine production (notably TNF-a and IL-1�). In recent years, biotherapeutic treatments have provided clinical validation for anti-cytokine approaches to treating rheumatoid arthritis, Crohn's disease and psoriasis. Small molecule-based inhibition of p38a as an alternative approach to block production of these cytokines offers the potential benefits of reduced cost and ease of administration. These aspects, along with the ability to simultaneously affect multiple cytokines and inflammatory mediators, have stimulated continued efforts to develop safe, potent and orally active p38a inhibitors. Pyrrolo[2,1-f][1,2,4]triazine based analogs incorporating aryl and heteroaryl ketones at the C6 position have been prepared leading to potent inhibitors of p38a. The structure-activity relationships, pharmacokinetic properties, activity in a pharmacodynamic model and efficacy in a rodent model of rheumatoid arthritis will be presented.

Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38α MAP kinase inhibitors

240th National Meeting (2010)

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