Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects

Fanghui Han; Mengmeng Ning; Hua Cao; Yangliang Ye; Ying Feng; Ying Leng; Jianhua Shen

doi:10.1016/j.ejmech.2020.112619

Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects

Eur J Med Chem. 2020 Oct 1:203:112619. doi: 10.1016/j.ejmech.2020.112619. Epub 2020 Jul 12.

Authors

Fanghui Han¹, Mengmeng Ning², Hua Cao², Yangliang Ye², Ying Feng², Ying Leng³, Jianhua Shen⁴

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai, 201203, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: yleng@simm.ac.cn.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: jhshen@simm.ac.cn.

PMID: 32682201
DOI: 10.1016/j.ejmech.2020.112619

Abstract

The G-protein-coupled bile acid receptor TGR5 agonists were widely developed in type 2 diabetes and gastrointestinal disorders, but were also full of challenges, due to the systemic on-targeted side effects, especially the gallbladder-filling effects. Here, to circumvent these risks, several TGR5 agonists with soft-drug designation had been designed and synthesized with the properties of rapid metabolized after drug effect. Among them, compound 19 showed negligible systemic exposure and favorable gallbladder safety on a 3-day continuous administration, providing a novel strategy for developing TGR5 agonists.

Keywords: Carboxylic ester; GLP-1; Gallbladder-filling effects; Rapid metabolism; Soft drug; TGR5.

MeSH terms

Animals
Drug Design*
Gallbladder / drug effects
Gallbladder / metabolism*
Humans
Male
Mice
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / metabolism
Pyridines / pharmacology
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / metabolism*
Risk

Substances

GPBAR1 protein, human
Pyridines
Receptors, G-Protein-Coupled
pyridine