2. Academic Validation
  3. The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy

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

Affiliation

  • 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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