The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38α MAPK and phosphodiesterase 4 (PDE4), and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs, and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha release. For reconfirming the findings of the animal studies when administering 1 to healthy human volunteers, a phase I clinical trial was conducted. Apart from further information regarding the pharmacokinetic and pharmacodynamic characteristics of 1, it was demonstrated that dual inhibition of p38α MAPK and PDE4 is able to synergistically attenuate the excessive anti-inflammatory response.

译文

p38丝裂原活化蛋白激酶 (MAPK) 抑制剂的抗炎潜力被巧合地扩展为对p38α MAPK和磷酸二酯酶4 (PDE4) 的双重抑制,并且两种炎症相关酶的阻断所产生的潜在益处被彻底研究。在对啮齿动物,狗和猴子施用1之后,在体外实验以及体外和体内临床前研究中相继评估了最有希望的化合物CBS-3595 (1)。所得数据清楚地表明有效抑制了肿瘤坏死因子 α 的释放。为了在向健康的人类志愿者施用1时再次确认动物研究的结果,进行了I期临床试验。除了有关1的药代动力学和药效学特征的进一步信息外,还证明了p38α MAPK和PDE4的双重抑制能够协同减弱过度的抗炎反应。

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