Jiao Shixuan, Ren Qiang, Chen Lianru, Zhou Zongtao, Cai Zongyu, Huang Wanqiu, Wang Bin, Chen Siliang, Wang Wenxin, Cao Zhijun, Yang Zhongcheng, Ye Qiqing, Zhang Luyong, Li Zheng
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China.
Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China.
J Med Chem. 2025 Mar 27;68(6):6127-6148. doi: 10.1021/acs.jmedchem.4c02720. Epub 2025 Jan 24.
Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease driven by diverse metabolic and inflammatory pathways. Farnesoid X receptor (FXR) is a promising target for MASH due to its role in bile acid and lipid metabolism, while HSD17B13 regulates liver lipid droplet homeostasis. However, the existing HSD17B13 inhibitors have several druglike property challenges due to the common phenolic structure, a key pharmacophore for the HSD17B13 inhibitor. In this study, a two-round high-throughput screening was performed to identify the FXR agonist as the nonphenolic HSD17B13 inhibitor. The multiparameter structural optimization led to the discovery of dual FXR/HSD17B13 modulator , with high target selectivity, target tissue distribution, suitable pharmacokinetic properties, and safety profiles. Moreover, even at the lower dose, compound exerted a better therapeutic effect than obeticholic acid (OCA) in multiple MASH models. With attractive pharmacological activity and safety profiles, the dual FXR/HSD17B13 modulator is worthy of further evaluation as a novel anti-MASH agent.
代谢功能障碍相关脂肪性肝炎（MASH）是一种由多种代谢和炎症途径驱动的复杂疾病。法尼酯X受体（FXR）因其在胆汁酸和脂质代谢中的作用，是治疗MASH的一个有前景的靶点，而17β-羟类固醇脱氢酶13（HSD17B13）调节肝脏脂质滴稳态。然而，由于HSD17B13抑制剂常见的酚类结构（HSD17B13抑制剂的关键药效团），现有的HSD17B13抑制剂存在一些类药性质方面的挑战。在本研究中，进行了两轮高通量筛选，以鉴定FXR激动剂作为非酚类HSD17B13抑制剂。多参数结构优化导致发现了双FXR/HSD17B13调节剂，其具有高靶点选择性、靶点组织分布、合适的药代动力学性质和安全性。此外，即使在较低剂量下，化合物在多个MASH模型中也比奥贝胆酸（OCA）发挥更好的治疗效果。鉴于具有吸引人的药理活性和安全性，双FXR/HSD17B13调节剂作为一种新型抗MASH药物值得进一步评估。
