Donauklinik Neu-Ulm, Abteilung für Innere Medizin, Neu-Ulm, Germany.
Institute of Physiological Chemistry, Ulm University, Ulm, Germany.
PLoS One. 2020 Jul 23;15(7):e0235990. doi: 10.1371/journal.pone.0235990. eCollection 2020.
Alcoholic steatohepatitis (ASH)-the inflammation of fatty liver-is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation-the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH.
In this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies.
A new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol.
Due to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH.
酒精性脂肪性肝炎（ASH）——即脂肪肝炎症，由慢性酒精摄入引起，是西方国家主要的慢性肝病之一。ASH 可导致器官功能障碍或进展为肝细胞癌（HCC）。长期戒酒可降低这种可能性，也是肝移植的前提条件——目前唯一有效的治疗选择。已知细胞色素 P450 2E1（CYP2E1）的酶活性升高与 ASH 的发展密切相关，因为在乙醇代谢过程中会产生过高水平的活性氧（ROS）。迄今为止，尚未成功启动针对 CYP2E1 的合理药物发现过程来治疗 ASH。
在这项研究中，我们应用了合理的药物设计概念来开发药物候选物（NCE），并进行了临床前研究。
成功生成了一类新的药物候选物。在药物发现和可开发性的过程结束时，选择了两种最有前途的小分子化合物，分别是 12-咪唑基-1-十二醇（简称：I-ol）和 1-咪唑基十二烷（简称：I-an）。这些新的ω-咪唑基-烷基衍生物在纳摩尔范围内作为强嵌合 CYP2E1 抑制剂发挥作用。它们恢复了氧化还原平衡，减少了炎症过程和肝脏中的脂肪含量，并挽救了持续大量饮酒的大鼠的生理肝脏结构。
由于其口服应用和优于肝保护剂熊去氧胆酸（UDCA）的治疗优势，这种新的抑制剂类标志着 ASH 长期治疗的第一个合理的药物概念。
