Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes

Hongliang Duan, Mengmeng Ning, Qingan Zou, Yangliang Ye, Ying Feng, Lina Zhang, Ying Leng, Jianhua Shen

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)


Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 Å2, and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.

Original languageEnglish
Pages (from-to)3315-3328
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number8
Publication statusPublished - 23 Apr 2015
Externally publishedYes


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