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

  • Bioorg Med Chem. 2001 Feb;9(2):537-54. doi: 10.1016/s0968-0896(00)00331-x.
L M Mclay  1 ,  F Halley ,  J E Souness ,  J McKenna ,  V Benning ,  M Birrell ,  B Burton ,  M Belvisi ,  A Collis ,  A Constan ,  M Foster ,  D Hele ,  Z Jayyosi ,  M Kelley ,  C Maslen ,  G Miller ,  M C Ouldelhkim ,  K Page ,  S Phipps ,  K Pollock ,  B Porter ,  A J Ratcliffe ,  E J Redford ,  S Webber ,  B Slater ,  V Thybaud ,  N Wilsher
Affiliations
  • 1. Aventis, Dagenham Research Centre, Essex, UK.
PMID: 11249145 DOI: 10.1016/s0968-0896(00)00331-x
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.

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