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 <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>

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 <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>

Design, Synthesis, and Antidiabetic Activity of 4‑Phenoxynicotinamide and 4‑Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists

4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC₅₀ values in the low nanomolar range. Compound <b>23g</b>, with an EC₅₀ value of 0.72 nM on hTGR5 and an EC₅₀ value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of <b>23g</b> (50 mg/kg) significantly reduced blood glucose levels in <i>db/db</i> mice and caused a 49% reduction in the area under the blood glucose curve (AUC)_0–120 min following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, <b>23g</b> stimulated gallbladder filling, which might result in side effects to the gallbladder