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

被引：76

作者：

McLay, IM ^{[1
]}

Halley, F ^{[1
]}

Souness, JE ^{[1
]}

McKenna, J ^{[1
]}

Benning, V ^{[1
]}

Birrell, M ^{[1
]}

Burton, B ^{[1
]}

Belvisi, M ^{[1
]}

Collis, A ^{[1
]}

Constan, A ^{[1
]}

Foster, M ^{[1
]}

Hele, D ^{[1
]}

Jayyosi, Z ^{[1
]}

Kelley, M ^{[1
]}

Maslen, C ^{[1
]}

Miller, G ^{[1
]}

Ouldelhkim, MC ^{[1
]}

Page, K ^{[1
]}

Phipps, S ^{[1
]}

Pollock, K ^{[1
]}

Porter, B ^{[1
]}

Ratcliffe, AI ^{[1
]}

Redford, EJ ^{[1
]}

Webber, S ^{[1
]}

Slater, B ^{[1
]}

Thybaud, V ^{[1
]}

Wilsher, N ^{[1
]}

机构：

[1] Aventis, Dagenham Res Ctr, Dagenham RM10 7XS, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2001年 / 9卷 / 02期

关键词：

D O I：

10.1016/S0968-0896(00)00331-X

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 TNF alpha 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. (C) 2001 Elsevier Science Ltd. All rights reserved.

引用

页码：537 / 554

页数：18

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