Foster M L, Halley F, Souness J E
AstraZeneca R&D Charnwood, Pathology, Loughborough, UK.
Drug News Perspect. 2000 Oct;13(8):488-97.
Rheumatoid arthritis (RA) is a chronic debilitating disease estimated to afflict 13% of the world population. Although palliative treatments (nonsteroidal antiinflammatory drugs or NSAIDs) are widely prescribed, there are currently only a few treatments that can modify the insidious progression of the disease (disease-modifying antirheumatic drugs or DMARDs), which frequently leads to physical incapacitation and, on occasion, death. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are implicated in the disease onset and in the progression of bone and joint destruction that characterizes chronic RA. p38 is an intracellular mitogen/stress-activated protein kinase (MAPK/SAPK) that regulates both the release and the actions of TNF-alpha and IL-1 beta. Inhibition of p38 kinase is thus an important potential target for novel DMARDs. Following the pioneering work conducted at SmithKline Beecham and elucidation of the roles of p38 with potent and selective inhibitors such as SB-203580, many pharmaceutical companies have embarked upon p38 synthetic programs, as indicated by the ever-increasing number of patents in this domain. At Aventis, a rapid parallel synthesis project led to the identification of RPR-200765A, a potent and selective p38 inhibitor of the lipopolysaccharide-induced release of TNF-alpha in vitro in mononuclear phagocytes and in vivo in the rat. It also reduces disease incidence and progression in the rat streptococcal cell wall arthritis model when administered orally in either a prophylactic or a therapeutic dosing regimen. Development of p38 inhibitors has been slow, probably because of toxicological problems, which might explain why only two oral p38 inhibitors, SB-242235 and VX-745, have advanced into clinical development. In the present article, the preclinical data exemplified in studies on RPR-200765A indicating why p38 inhibitors are attracting so much attention as potential novel anti-RA drugs are reviewed. Current information on the different structural classes of p38 inhibitors is presented and possible reasons for the delays in their development are critically discussed.
类风湿性关节炎（RA）是一种慢性致残性疾病，估计全球有13%的人口受其折磨。尽管姑息性治疗（非甾体抗炎药或NSAIDs）被广泛应用，但目前只有少数几种治疗方法能够改变这种疾病的隐匿性进展（改善病情抗风湿药或DMARDs），该病常常导致身体残疾，有时甚至会导致死亡。促炎细胞因子如肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）与疾病的发生以及慢性RA所特有的骨和关节破坏的进展有关。p38是一种细胞内丝裂原/应激激活蛋白激酶（MAPK/SAPK），可调节TNF-α和IL-1β的释放及作用。因此，抑制p38激酶是新型DMARDs的一个重要潜在靶点。继史克必成公司开展开拓性工作并利用SB-203580等强效选择性抑制剂阐明p38的作用之后，许多制药公司纷纷启动了p38合成项目，这一领域的专利数量不断增加就表明了这一点。在安万特公司，一个快速平行合成项目导致发现了RPR-200765A，它是一种强效选择性p38抑制剂，在体外单核吞噬细胞中以及在大鼠体内均可抑制脂多糖诱导的TNF-α释放。当以预防或治疗给药方案口服时，它还能降低大鼠链球菌细胞壁关节炎模型中的疾病发病率和疾病进展。p38抑制剂的研发进展缓慢，可能是由于毒理学问题，这或许可以解释为何只有两种口服p38抑制剂SB-242235和VX-745进入了临床开发阶段。在本文中，将对以RPR-200765A研究为例的临床前数据进行综述，这些数据表明了p38抑制剂作为潜在新型抗RA药物为何如此受关注。文中介绍了p38抑制剂不同结构类别的当前信息，并对其研发延迟的可能原因进行了批判性讨论。
