Therapeutic Potential of p38 MAP Kinase Inhibition in the Management of Cardiovascular Disease
Therapeutic Potential of p38 MAP Kinase Inhibition in the Management of Cardiovascular Disease
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DOI：
10.1007/s40256-014-0063-6
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发表时间：
2014-06-01
影响因子：
3
通讯作者：
Cheriyan, Joseph
中科院分区：
文献类型：
--
作者：
Fisk, Marie;Gajendragadkar, Parag R.;Cheriyan, Joseph
p38丝裂原活化蛋白激酶（p38 MAPKs）是调节细胞响应环境胁迫行为的关键信号分子。它们调节促炎细胞因子，因此p38 MAPKs与许多炎症驱动的疾病（包括动脉粥样硬化）的发病机制有关。随着p38 α被发现是pyrindinyl咪唑化合物的分子靶点，抑制肿瘤坏死因子- α和白细胞介素-1的细胞因子，治疗性抑制p38 MAPKs以减轻炎症已成为过去20年全面研究的重点。p38 MAPK抑制剂的潜力最初是在类风湿关节炎和克罗恩病等典型炎症条件下探索的，但早期研究表明临床疗效不佳，副作用不可接受。随后的临床试验评估了不同的p38 MAPK抑制剂化合物在慢性阻塞性肺疾病（COPD）和动脉粥样硬化等疾病模型中的潜在临床疗效。本文旨在提供关于p38 MAPK信号通路的简明背景信息，p38 MAPK在疾病中的重点，以及相关临床前研究的简要总结。人类临床试验经验的更新，包括临床导向的方法，致力于心血管疾病如下。它提供了p38 MAPK抑制剂在心血管领域的治疗潜力的当前观点，包括安全性，耐受性和药代动力学。
p38 mitogen-activated protein kinases (p38 MAPKs) are key signalling molecules that regulate cellular behavior in response to environmental stresses. They regulate pro-inflammatory cytokines and therefore p38 MAPKs are implicated in the pathogenesis of many inflammatory-driven conditions, including atherosclerosis. Therapeutic inhibition of p38 MAPKs to attenuate inflammation has been the focus of comprehensive research in the last 2 decades, following the discovery of p38 alpha as the molecular target of pyrindinyl imidazole compounds, which suppress the cytokines tumor necrosis factor-alpha and interleukin-1. The potential of p38 MAPK inhibitors was initially explored within archetypal inflammatory conditions such as rheumatoid arthritis and Crohn's disease, but early studies demonstrated poor clinical efficacy and unacceptable side effects. Subsequent clinical trials evaluating different p38 MAPK inhibitor compounds in disease models such as chronic obstructive pulmonary disease (COPD) and atherosclerosis have shown potential clinical efficacy. This review aims to provide succinct background information regarding the p38 MAPK signaling pathway, a focus of p38 MAPKs in disease, and a brief summary of relevant pre-clinical studies. An update of human clinical trial experience encompassing a clinically orientated approach, dedicated to cardiovascular disease follows. It provides a current perspective of the therapeutic potential of p38 MAPK inhibitors in the cardiovascular domain, including safety, tolerability, and pharmacokinetics.