Discovery of HPG1860, a Structurally Novel Nonbile Acid FXR Agonist Currently in Clinical Development for the Treatment of Nonalcoholic Steatohepatitis

被引：14

作者：

Mo, Cheng ^{[1
]}

Xu, Xiaoqing ^{[1
]}

Zhang, Pan ^{[1
]}

Peng, Yihong ^{[1
]}

Zhao, Xinpeng ^{[1
]}

Chen, Shijia ^{[1
]}

Guo, Fang ^{[1
]}

Xiong, Yating ^{[1
]}

Chu, Xin-Jie ^{[1
]}

Xu, Xiaodong ^{[1
]}

机构：

[1] Hepagene Therapeut Inc, Suzhou 215123, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 14期

关键词：

FARNESOID-X-RECEPTOR; NUCLEAR RECEPTOR; BILE-ACID; OBETICHOLIC ACID; ACTIVATED RECEPTORS; IDENTIFICATION; MULTICENTER; METABOLISM; EXPRESSION; DIAGNOSIS;

D O I：

10.1021/acs.jmedchem.3c00456

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

The farnesoid X receptor (FXR) is a ligand-activatednuclear receptor.Activation of FXR significantly impacts the expressions of the pivotalgenes involved in bile acid metabolism, inflammation, fibrosis, andhomeostasis of lipid and glucose, leading to considerable interestsin developing FXR agonists for the treatment of nonalcoholic steatohepatitis(NASH) or other FXR-relevant diseases. Herein, we describe the design,optimization, and characterization of a series of N-methylene-piperazinyl derivatives as the nonbile acid FXR agonists.Particularly, compound 23 (HPG1860), a potentfull FXR agonist, shows high selectivity, favorable ADME and pharmacokineticsprofile, along with favorable in vivo activitiesdemonstrated in both rodent PD model and HFD-CCl4 modeland is currently in clinical development in patients with NASH inphase II.

引用

页码：9363 / 9375

页数：13

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