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Abstract：
BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we report the synthesis and the biological evaluation of a library of hybrid compounds prepared by combining, through high-yield condensation reaction, some fibrates with BAR502.The activity of the new conjugates was evaluated towards FXR, GPBAR1 and PPARα receptors, employing transactivation or cofactor recruitment assays. Compound 1 resulted as the most promising of the series and was subjected to further pharmacological investigation, together with stability evaluation and cell permeation assessment. We have proved by LCMS analysis that compound 1 is hydrolyzed in mice releasing clofibric acid and BAR505, the oxidized metabolite of BAR502, endowed with retained dual FXR/GPBAR1 activity.
摘要：
BAR502，一种胆汁酸类似物，作为FXR/GPBAR1双重激动剂具有活性，并且代表了治疗胆汁淤积和NASH的有希望的线索。在本文中，我们报告了通过结合制备的杂化化合物库的合成和生物学评价，通过高产率的缩合反应，一些贝特类药物与BAR502。评估新缀合物针对FXR的活性，GPBAR1和PPARα受体，采用反式激活或辅因子募集测定。化合物1作为该系列中最有前途的化合物，并进行了进一步的药理学研究，以及稳定性评估和细胞渗透评估。我们通过LCMS分析证明，化合物1在小鼠中水解，释放出氯贝特酸和BAR505，即BAR502的氧化代谢产物，具有保留的FXR/GPBAR1双重活性。
