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Synthesis and evaluation of substituted phenyl cycloalkylureas and bioisosteres as IL-6 expression inhibitors
Medicinal Chemistry Research ( IF 2.6 ) Pub Date : 2020-05-19 , DOI: 10.1007/s00044-020-02557-w
Sébastien Tremblay , Joël Boutin , Martin Perreault , Marie-France Côté , Stéphane Gobeil , René C.-Gaudreault

Inflammation is an important, normal, and complex host defense response to injury, autoimmune responses or infectious agents. However, chronic inflammation is associated with diseases like rheumatoid arthritis, cancers, cardiovascular diseases, diabetes, and obesity, and over 60% of deaths worldwide. Interleukine-6 is one of the key proinflammatory cytokines involved in inflammation processes and therefore considered as a valuable drug target. We have prepared three series of new drugs referred to as substituted phenyl cycloalkylureas (PcAUs), phenyl cycloalkylthioureas (PcATUs) and phenyl cycloalkylsquaramides (PcASs), respectively. PcAUs and PcATUs were prepared by nucleophilic addition of 3 or 4-tert-butyl, 3- or 4-cyclohexyl and 3- or 4-iodoaniline to a suitable cycloalkylisocyanate or cycloalkylisothiocyanate. PcASs were prepared by nucleophilic addition of the aforementioned anilines to diethoxysquarate. The resulting alkoxysquarates were further reacted with selected cycloalkylamines to produce the desired PcASs. The antiproliferative activity of PcAUs, PcATUs and PcASs was evaluated in human keratinocytes and human skin fibroblasts. Most compounds at the exception of 4f, 4f′, 4f″, 5f, 5f′, 5f″, 6f, and 6f′, 6f″ that are bearing a 3-cyclohexyl group did not exhibit significant antiproliferative activities at concentration <30 µM. At 10 µM, PcAUs 4b-4e, 5b, 5e, and 6e inhibited IL-6 expression by more than 70% in HaCaT cells, which is equivalent to or greater than ibuprofen used as a positive control. These PcAUs showed a good metabolic stability in presence of human liver microsomes. Our results are suggesting PcAUs as a new molecular template for the development of potentially useful IL-6 expression inhibitors for the treatment of inflammation-related diseases.

中文翻译:

IL-6表达抑制剂取代苯基环烷基脲和生物异构体的合成与评价

炎症是对损伤,自身免疫反应或感染因子的重要,正常和复杂的宿主防御反应。但是,慢性炎症与类风湿性关节炎,癌症,心血管疾病,糖尿病和肥胖症等疾病相关,并且与全世界60%以上的死亡有关。Interleukine-6是参与炎症过程的关键促炎细胞因子之一,因此被认为是有价值的药物靶标。我们已经制备了三种新药,分别称为取代的苯基环烷基脲(PcAUs),苯基环烷基硫脲(PcATUs)和苯基环烷基四酰胺(PcASs)。通过将3或4-叔丁基,3-或4-环己基和3-或4-碘苯胺亲核加成到合适的环烷基异氰酸酯或环烷基异硫氰酸酯来制备PcAU和PcATU。通过将上述苯胺亲二加到二乙氧基方酸中来制备PcAS。使所得的烷氧基方酸酯进一步与选择的环烷基胺反应以产生所需的PcAS。在人角质形成细胞和人皮肤成纤维细胞中评估了PcAUs,PcATUs和PcASs的抗增殖活性。除以下化合物外,大多数化合物带有3-环己基的4f4f′4f″5f5f′5f″6f6f′6f″在浓度<30μM时没有表现出显着的抗增殖活性。在10 µM时,PcAU 4b-4e5b5e6e在HaCaT细胞中抑制IL-6的表达超过70%,这等于或大于用作阳性对照的布洛芬。这些PcAUs在人肝微粒体存在下显示出良好的代谢稳定性。我们的结果表明,PcAUs作为开发潜在有用的IL-6表达抑制剂来治疗炎症相关疾病的新分子模板。
更新日期:2020-05-19
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