343304-85-8Relevant articles and documents
The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy
McLay, Iain M.,Halley, Frank,Souness, John E.,McKenna, Jeffrey,Benning, Veronique,Birrell, Mark,Burton, Brenda,Belvisi, Maria,Collis, Alan,Constan, Alex,Foster, Martyn,Hele, David,Jayyosi, Zaid,Kelley, Mike,Maslen, Chris,Miller, Glen,Ouldelhkim, Marie-Claude,Page, Kenneth,Phipps, Simon,Pollock, Kenneth,Porter, Barry,Ratcliffe, Andrew J.,Redford, Elisabeth J.,Webber, Stephen,Slater, Bryan,Thybaud, Veronique,Wilsher, Nicola
, p. 537 - 554 (2001)
RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)α release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFα release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 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 prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.