As a member of the nuclear receptor superfamily, the farnesoid X receptor (FXR) is a bile acid activated transcription factor. FXR is involved in many important metabolic processes and serves as a promising therapeutic target for nonalcoholic steatohepatitis (NASH). Since discovered, the first non-steroidal FXR agonist GW4064 has been widely used to explore the biological functions of FXR, however, the low pharmacokinetic limited its further clinical application. In current study, we designed a series of substituted isothiazoles as new FXR agonists. Among them, five compounds exhibited better FXR agonistic activity than GW4064. Specially, the most potent compound S5 possessed better pharmacokinetic profile and in vivo potency than lead compound.

作为核受体超家族的成员，法尼醇 X 受体 (FXR) 是一种胆汁酸激活的转录因子。FXR 参与许多重要的代谢过程，是非酒精性脂肪性肝炎 (NASH) 的有希望的治疗靶点。自发现以来，第一个非甾体FXR激动剂GW4064已被广泛用于探索FXR的生物学功能，但其较低的药代动力学限制了其进一步的临床应用。在目前的研究中，我们设计了一系列取代的异噻唑作为新的 FXR 激动剂。其中，五种化合物表现出比GW4064更好的FXR激动活性。特别是，最有效的化合物S5比先导化合物具有更好的药代动力学特征和体内效力。