VX-745, a lead anti-inflammatory candidate, small-molecule inhibitor of mitogen-activated protein kinase (MAPK), is under development by Vertex Pharmaceuticals Inc in association with Kissei Pharmaceutical Co Ltd for the potential treatment of rheumatoid arthritis (RA) [214928]. VX-745 was introduced by Vertex as a potential antiinflammatory drug for the treatment of RA in a pilot phase II trial initiated in November 1999 [346067]. In June 2000, phase II trials were still ongoing [371819] and in January 2001, Vertex initiated a randomized, double-blind, placebo-controlled phase II trial in adult patients with RA, with the objective of evaluating clinical response rates, self-reported patient health assessments and pharmacodynamic markers of drug activity [395083]. During the 33rd Annual Meeting of the American Chemical Society in May 2000, VX-745 was reported to be active against several isotypes of p38 MAPK, including p38alpha, p38beta and p38gamma [368149]. The targeting of p38 MAPK by VX-745 was associated with the suppression of the release of inflammatory mediators, including interleukin (IL)-1beta and tumor necrosis factor (TNF)alpha, known to be implicated in exacerbating the pathophysiology of RA [273648], [368149], [371548], [372054], [408713].