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

McLay, I. 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. I., Redford, E. J., Webber, S., Slater, B., Thybaud, V. and Wilsher, N. (2001) The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy. Bioorganic & Medicinal Chemistry, 9 2: 537-554. doi:10.1016/S0968-0896(00)00331-X

Author McLay, I. 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. I.
Redford, E. J.
Webber, S.
Slater, B.
Thybaud, V.
Wilsher, N.
Title The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy
Journal name Bioorganic & Medicinal Chemistry   Check publisher's open access policy
ISSN 0968-0896
Publication date 2001-02
Sub-type Article (original research)
DOI 10.1016/S0968-0896(00)00331-X
Volume 9
Issue 2
Start page 537
End page 554
Total pages 18
Place of publication Oxford, United Kingdom
Publisher Pergamon
Language eng
Abstract 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
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Created: Wed, 09 Mar 2011, 14:30:16 EST