The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a goodoral anti-arthritic efficacy

RPR132331, a 2-(2-dioxanyl)imidazole. was identified as an inhibitor of tum our necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimul ated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived f rom RPR132331, has led to the identification of RPR200765A, a development c andidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a po tent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNF alpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses betwe en 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either p rophylactic or therapeutic dosing regimens. The compound, which is a mesyla te salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the S CW disease model suggests that RPR200765A could exhibit a profile of diseas e modifying activity in rheumatoid arthritis (RA) patients which is not obs erved with current drug therapies. (C) 2001 Elsevier Science Ltd. All right s reserved.