Design, synthesis and biological evaluations of novel farnesoid X receptor (FXR) agonists

Yuanju Zhu; Jay Zhang; Feng Min; Xinying Yang; Li Li; Yan Zhang; Xuben Hou; Hao Fang

doi:10.1016/j.bmcl.2022.128993

Design, synthesis and biological evaluations of novel farnesoid X receptor (FXR) agonists

Bioorg Med Chem Lett. 2022 Nov 15:76:128993. doi: 10.1016/j.bmcl.2022.128993. Epub 2022 Sep 18.

Authors

Yuanju Zhu¹, Jay Zhang², Feng Min³, Xinying Yang⁴, Li Li², Yan Zhang², Xuben Hou⁴, Hao Fang⁵

Affiliations

¹ Institute of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Wenhuaxi Road 44, Jinan 250012, China; KBP Biosciences, 401, Building 2, Jinan Pharm Valley, North Section of Gangxing Three Road, Jinan, Shandong 250101, China.
² KBP Biosciences, 401, Building 2, Jinan Pharm Valley, North Section of Gangxing Three Road, Jinan, Shandong 250101, China.
³ High School Attached to Shandong Normal University, No.3 North Shanshi Street, Jinan 200514, China.
⁴ Institute of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Wenhuaxi Road 44, Jinan 250012, China.
⁵ Institute of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Wenhuaxi Road 44, Jinan 250012, China. Electronic address: haofangcn@sdu.edu.cn.

PMID: 36130662
DOI: 10.1016/j.bmcl.2022.128993

Abstract

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.

Keywords: FXR agonist; Farnesoid X receptor; Non-alcoholic steatohepatitis (NASH); Non-steroid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Acids and Salts / therapeutic use
Gene Expression Regulation
Humans
Non-alcoholic Fatty Liver Disease* / drug therapy
Receptors, Cytoplasmic and Nuclear*
Transcription Factors

Substances

Receptors, Cytoplasmic and Nuclear
Bile Acids and Salts
Transcription Factors