Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes

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.