The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy |
| |
Authors: | Mclay L M Halley F Souness J E McKenna J Benning V Birrell M Burton B Belvisi M Collis A Constan A Foster M Hele D Jayyosi Z Kelley M Maslen C Miller G Ouldelhkim M C Page K Phipps S Pollock K Porter B Ratcliffe A J Redford E J Webber S Slater B Thybaud V Wilsher N |
| |
Affiliation: | Aventis, Dagenham Research Centre, Essex, UK. |
| |
Abstract: | RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha 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 TNFalpha 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. |
| |
Keywords: | |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|