Albrecht Wolfgang, Unger Anke, Bauer Silke M, Laufer Stefan A
c-a-i-r biosciences GmbH , Alfred-Mendler Weg 25/1, D-89075 Ulm, Germany.
Eberhard Karls University Tuebingen , Department Pharmacy & Biochemistry, Pharmaceutical and Medicinal Chemistry, Auf der Morgenstelle 8, D-72076 Tuebingen, Germany.
J Med Chem. 2017 Jul 13;60(13):5290-5305. doi: 10.1021/acs.jmedchem.6b01647. Epub 2017 Jun 27.
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.
p38丝裂原活化蛋白激酶（MAPK）抑制剂的抗炎潜力意外地扩展为对p38α MAPK和磷酸二酯酶4（PDE4）的双重抑制，并且对阻断这两种炎症相关酶所产生的潜在益处进行了深入研究。最有前景的化合物CBS-3595（1）在给予啮齿动物、狗和猴子1后，先后在体外实验以及离体和体内临床前研究中进行了评估。所得数据清楚地表明其对肿瘤坏死因子α释放有强力抑制作用。为了在将1给予健康人类志愿者时再次确认动物研究的结果，进行了一项I期临床试验。除了关于1的药代动力学和药效学特征的更多信息外，还证明了对p38α MAPK和PDE4的双重抑制能够协同减弱过度的抗炎反应。
