当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Discovery of N-{4-[5-(4-Fluorophenyl)-3-methyl-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide (CBS-3595), a Dual p38α MAPK/PDE-4 Inhibitor with Activity against TNFα-Related Diseases
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-06-27 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01647 Wolfgang Albrecht 1 , Anke Unger 1 , Silke M. Bauer 2 , Stefan A. Laufer 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-06-27 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01647 Wolfgang Albrecht 1 , Anke Unger 1 , Silke M. Bauer 2 , Stefan A. Laufer 2
Affiliation
|
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.
中文翻译：
的发现ñ - {4- [5-（4-氟苯基）-3-甲基-2-甲硫基- 3 H ^ -咪唑-4-基] -吡啶-2-基} -乙酰胺（CBS-3595），在双具有抗TNFα相关疾病活性的p38αMAPK / PDE-4抑制剂
同时将p38丝裂原活化蛋白激酶（MAPK）抑制剂的抗炎潜力扩大到对p38αMAPK和磷酸二酯酶4（PDE4）的双重抑制作用，并全面研究了由两种炎症相关酶的阻断引起的潜在益处。 。给啮齿动物，狗和猴子施用1后，在体外实验以及离体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。用于在给药1时再次确认动物研究的结果针对健康的人类志愿者，进行了I期临床试验。除了关于所述药代动力学和药效学特性的进一步信息1，它证明了p38αMAPK的双重抑制和PDE4能够协同地衰减过度抗炎反应。
更新日期：2017-06-28
中文翻译：
的发现ñ - {4- [5-（4-氟苯基）-3-甲基-2-甲硫基- 3 H ^ -咪唑-4-基] -吡啶-2-基} -乙酰胺（CBS-3595），在双具有抗TNFα相关疾病活性的p38αMAPK / PDE-4抑制剂
同时将p38丝裂原活化蛋白激酶（MAPK）抑制剂的抗炎潜力扩大到对p38αMAPK和磷酸二酯酶4（PDE4）的双重抑制作用，并全面研究了由两种炎症相关酶的阻断引起的潜在益处。 。给啮齿动物，狗和猴子施用1后，在体外实验以及离体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。用于在给药1时再次确认动物研究的结果针对健康的人类志愿者，进行了I期临床试验。除了关于所述药代动力学和药效学特性的进一步信息1，它证明了p38αMAPK的双重抑制和PDE4能够协同地衰减过度抗炎反应。
京公网安备 11010802027423号