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
Aventis, Dagenham Research Centre, Essex, UK.
Bioorg Med Chem. 2001 Feb;9(2):537-54. doi: 10.1016/s0968-0896(00)00331-x.
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.
RPR132331，一种2-(2-二氧杂环己烷基)咪唑，被鉴定为脂多糖(LPS)刺激的人单核细胞中肿瘤坏死因子(TNF)α释放的抑制剂。一项深入的研究工作，探索了一系列源自RPR132331的新型抑制剂的生物学、毒性和物理化学性质，从而确定了RPR200765A，一种用于治疗类风湿性关节炎(RA)的候选开发药物。RPR200765A是一种强效且选择性的p38丝裂原活化蛋白激酶抑制剂(IC50 = 50 nM)。它在体外能抑制人单核细胞中LPS刺激的TNFα释放(EC50 = 110 nM)，在体内对Balb/c小鼠也有抑制作用(ED50 = 6 mg/kg)。在大鼠链球菌细胞壁(SCW)关节炎模型中，当以10至30 mg/kg/天的口服剂量给药时（无论是预防性还是治疗性给药方案），它能降低发病率和疾病进展。该化合物为甲磺酸盐，以稳定的一水合物形式存在，具有良好的口服生物利用度(大鼠体内F = 50%)和出色的化学稳定性。来自SCW疾病模型的数据表明，RPR200765A在类风湿性关节炎(RA)患者中可能展现出一种目前药物疗法未观察到的疾病修饰活性特征。
