Topical Intestinal Aminoimidazole Agonists of G‑Protein-Coupled Bile Acid Receptor 1 Promote Glucagon Like Peptide‑1 Secretion and Improve Glucose Tolerance

The
role of the G-protein-coupled bile acid receptor TGR5 in various
organs, tissues, and cell types, specifically in intestinal endocrine
L-cells and brown adipose tissue, has made it a promising therapeutical
target in several diseases, especially type-2 diabetes and metabolic
syndrome. However, recent studies have shown deleterious on-target
effects of systemic TGR5 agonists. To avoid these systemic effects
while stimulating glucagon-like peptide-1 (GLP-1) secreting enteroendocrine
L-cells, we have designed TGR5 agonists with low intestinal permeability.
In this article, we describe their synthesis, characterization, and
biological evaluation. Among them, compound 24 is a potent
GLP-1 secretagogue, has low effect on gallbladder volume, and improves
glucose homeostasis in a preclinical murine model of diet-induced
obesity and insulin resistance, making the proof of concept of the
potential of topical intestinal TGR5 agonists as therapeutic agents
in type-2 diabetes.