Tateishi Yasuhiro, Ohe Tomoyuki, Ogawa Mai, Takahashi Kyoko, Nakamura Shigeo, Mashino Tadahiko
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Department of Chemistry, Nippon Medical School, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-0023, Japan.
ACS Omega. 2020 Dec 8;5(50):32608-32616. doi: 10.1021/acsomega.0c04942. eCollection 2020 Dec 22.
Diclofenac (DCF) is widely used as a nonsteroidal anti-inflammatory drug; however, it is associated with severe liver injury. This adverse reaction is thought to be related to the reactive quinone imine (QI) and acyl glucuronide (AG) metabolites of DCF, but it remains controversial which reactive metabolites mainly contribute to DCF-induced toxicity. In this study, we synthesized five types of DCF analogs that were designed to mitigate the formation of reactive QI and/or AG metabolites and evaluated their metabolic stability, cyclooxygenase (COX) inhibitory activity, and toxicity to cryopreserved human hepatocytes. Compounds with fluorine at the 5- and 4'-positions of aromatic rings exhibited modest and high metabolic stability to oxidation by cytochrome P450, respectively, but induced cytotoxicity comparable to DCF. Replacing the carboxylic group of DCF with its bioisosteres was effective in terms of stability to oxidative metabolism and glucuronidation; however, sulfonic acid and sulfonamide groups were not preferable for COX inhibition, and tetrazole-containing analogs induced strong cytotoxicity. On the other hand, compounds that have fluorine at the benzylic position were resistant to glucuronidation and showed little toxicity to hepatocytes. In addition, among these compounds, those with hydrogen at the 4'-position ( and ) selectively inhibited the COX-2 enzyme. Throughout these data, it was suggested that compounds and might be novel safer and more efficacious drug candidates instead of DCF.
双氯芬酸（DCF）作为一种非甾体抗炎药被广泛使用；然而，它与严重的肝损伤有关。这种不良反应被认为与DCF的反应性醌亚胺（QI）和酰基葡萄糖醛酸（AG）代谢物有关，但哪种反应性代谢物主要导致DCF诱导的毒性仍存在争议。在本研究中，我们合成了五种类型的DCF类似物，旨在减少反应性QI和/或AG代谢物的形成，并评估了它们的代谢稳定性、环氧合酶（COX）抑制活性以及对冷冻保存的人肝细胞的毒性。在芳环的5-位和4'-位带有氟的化合物分别对细胞色素P450氧化表现出适度和高度的代谢稳定性，但诱导的细胞毒性与DCF相当。用其生物电子等排体取代DCF的羧基在氧化代谢和葡萄糖醛酸化稳定性方面是有效的；然而，磺酸和磺酰胺基团对COX抑制不太有利，含四唑的类似物诱导强烈的细胞毒性。另一方面，在苄基位置带有氟的化合物对葡萄糖醛酸化有抗性，对肝细胞几乎没有毒性。此外，在这些化合物中，在4'-位带有氢的那些化合物（和）选择性地抑制COX-2酶。综合这些数据表明，化合物和可能是比DCF更安全、更有效的新型候选药物。
