Norman Peter
Norman Consulting , 18 Pink Lane, Burnham, Bucks, SL1 8JW , UK
Expert Opin Investig Drugs. 2015 Mar;24(3):383-92. doi: 10.1517/13543784.2015.1006358. Epub 2015 Jan 20.
The p38 protein kinases, in particular p38α and p38β, regulate the production of multiple inflammatory mediators. Consequentially, considerable effort has been focused on trying to develop p38 inhibitors for the treatment of inflammatory diseases. Some 20 p38 inhibitors have progressed to clinical development, mostly for the treatment of rheumatoid arthritis, but with little success. Increasingly, interest has turned to their use in other indications and notably chronic obstructive pulmonary disease (COPD).
In this review, the author discusses the eight p38 inhibitors that have been clinically evaluated. Acumapimod is the only one of four orally delivered inhibitors that remains in active development while Phase II results of PH-797804 and losmapimod are compared. The activity of two inhibitors designed for inhaled delivery, RV-568 and PF-03715455, is compared but little is known about AZD-7624 or the discontinued GSK-610677.
Results from animal models provide a clear rationale for developing p38 inhibitors for COPD, and appear to be (partially) validated by the efficacy seen with PH-797804 and losmapimod. Inhaled delivery provides the opportunity to enhance p38 inhibition in the lung while reducing unwanted systemic effects of p38 inhibition. Validation of this hypothesis should come from the results of the recently completed Phase II study with RV-568.
p38蛋白激酶，尤其是p38α和p38β，可调节多种炎症介质的产生。因此，人们致力于开发p38抑制剂用于治疗炎症性疾病。约20种p38抑制剂已进入临床开发阶段，主要用于治疗类风湿性关节炎，但成效甚微。人们越来越关注它们在其他适应症中的应用，尤其是慢性阻塞性肺疾病（COPD）。
在本综述中，作者讨论了已进行临床评估的8种p38抑制剂。阿库马哌莫德是4种口服抑制剂中唯一仍在积极开发的药物，同时对PH-797804和洛索哌莫德的II期结果进行了比较。比较了两种吸入用抑制剂RV-568和PF-03715455的活性，但对AZD-7624或已停用的GSK-610677了解甚少。
动物模型的结果为开发用于COPD的p38抑制剂提供了明确的理论依据，并且PH-797804和洛索哌莫德的疗效似乎（部分）证实了这一点。吸入给药提供了增强肺部p38抑制作用同时减少p38抑制的不良全身效应的机会。这一假设的验证应来自最近完成的RV-568 II期研究的结果。
