Finamore Claudia, Festa Carmen, Barbato Rosa, Fiorucci Stefano, Zampella Angela, De Marino Simona
Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Naples, 80131, Italy.
Department of Medicine and Surgery, University of Perugia, Piazza L. Severi, 1, Perugia, 06132, Italy.
ChemMedChem. 2025 Aug 16;20(16):e202500405. doi: 10.1002/cmdc.202500405. Epub 2025 Jul 11.
Over the past decades, extensive scientific research in the fields of chemistry and pharmaceutical chemistry has led to the synthesis and study of numerous chemical compounds with diverse therapeutic applications. Many of these compounds feature heterocyclic aromatic structures, including four-, five-, and six-membered rings. Among them, five-membered heteroaromatic rings have garnered particular attention in medicinal chemistry due to their favorable properties, such as enhanced metabolic stability, solubility, and bioavailability, key attributes for the development of effective drugs. The distinctive physicochemical properties and biological activities of five-membered heterocycles have established them as vital structural motifs in numerous clinically effective drugs. These heterocyclic compounds play a crucial role in the design of therapeutic agents, including those targeting bile acid receptors. Bile acid receptor modulators, activated by endogenous bile acids, offer promising potential in treating a variety of metabolic and enterohepatic disorders, such as dyslipidemia, diabetes, cholestasis, and inflammatory bowel disease. This review aims to provide an up-to-date overview of aromatic five-membered nitrogen- and oxygen-containing heterocycles, focusing on their role as bile acid receptor modulators, particularly farnesoid X receptor and G protein-coupled bile acid receptor 1. These receptors are clinically validated targets for the treatment of metabolic disorders and nonalcoholic steatohepatitis.
在过去几十年中，化学和药物化学领域广泛的科学研究促使人们合成并研究了众多具有不同治疗应用的化合物。这些化合物中的许多都具有杂环芳香结构，包括四元、五元及六元环。其中，五元杂芳环因其良好的性质，如增强的代谢稳定性、溶解性和生物利用度（这些都是开发有效药物的关键属性），在药物化学中受到了特别关注。五元杂环独特的物理化学性质和生物活性使其成为众多临床有效药物中至关重要的结构基序。这些杂环化合物在治疗剂的设计中起着关键作用，包括那些靶向胆汁酸受体的药物。由内源性胆汁酸激活的胆汁酸受体调节剂在治疗多种代谢和肠肝疾病，如血脂异常、糖尿病、胆汁淤积和炎症性肠病方面具有广阔的潜力。本综述旨在提供关于芳香族五元含氮和含氧杂环的最新概述，重点关注它们作为胆汁酸受体调节剂的作用，特别是法尼酯X受体和G蛋白偶联胆汁酸受体1。这些受体是治疗代谢紊乱和非酒精性脂肪性肝炎的经临床验证的靶点。
