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

Abstract

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 <b>2</b> with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound <b>15c</b>, with a molecular weight of 1401, a PSA value of 223 Ų, and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of <b>15c</b> were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist <b>2</b>