A novel intestinal-restricted FXR agonist

Hong Wang; Zhou Zhao; Jiyu Zhou; Yitong Guo; Guangji Wang; Haiping Hao; Xiaowei Xu

doi:10.1016/j.bmcl.2017.06.003

A novel intestinal-restricted FXR agonist

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3386-3390. doi: 10.1016/j.bmcl.2017.06.003. Epub 2017 Jun 3.

Authors

Hong Wang¹, Zhou Zhao¹, Jiyu Zhou¹, Yitong Guo¹, Guangji Wang¹, Haiping Hao², Xiaowei Xu³

Affiliations

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang#24, Nanjing 210009, China; Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang#24, Nanjing 210009, China.
² State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang#24, Nanjing 210009, China; School of Pharmacy, China Pharmaceutical University, Tongjiaxiang#24, Nanjing 210009, China. Electronic address: haipinghao@cpu.edu.cn.
³ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang#24, Nanjing 210009, China; Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang#24, Nanjing 210009, China. Electronic address: xw@cpu.edu.cn.

PMID: 28629595
DOI: 10.1016/j.bmcl.2017.06.003

Abstract

In this study, a new intestinal-restricted FXR agonist named fexaramine-3 (Fex-3) was developed and investigated both in vitro and in vivo. Fex-3 could selectively activate intestinal FXR and promote the expression of BSEP and SHP while suppressing CYP7A1 which is involved in bile acids syntheses better than the reported intestinal-restricted FXR agonist fexaramine (Fex). We demonstrated that Fex-3 targeted on FXR in ileum and has better selectivity than Fex. And the study of utilizing Fex-3 to reduce obesity was undergoing.

Keywords: Agonist; Farnesoid X receptor; Fexaramine; Intestinal-restricted.

MeSH terms

Animals
Dose-Response Relationship, Drug
Humans
Intestines / drug effects*
Molecular Structure
Naphthalenes / chemical synthesis
Naphthalenes / chemistry
Naphthalenes / pharmacology*
Rats
Receptors, Cytoplasmic and Nuclear / agonists*
Structure-Activity Relationship

Substances

Naphthalenes
Receptors, Cytoplasmic and Nuclear
fexaramine-3
farnesoid X-activated receptor