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

Abstract

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.

Bile acids in glucose metabolism in health and disease

“…Thus, an ideal TGR5 agonist would be intestinal-specific agonist reaching L cells without affecting other systemic tissues. Indeed, Lasalle et al (2017) recently described a novel topical intestinal agonist of TGR5 that was given orally to obese and insulin-resistant mice, leading to prominent elevation in GLP-1 levels along with significant improvement in glucose tolerance. Intestinal TGR5 agonist did not cause a significant change in gallbladder size in lean mice.…”

Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1

“…Despite this promising anti-diabetic activity of TGR5 mediate by GLP-1 ( 345 ), its pharmacological activation in diabetic patients has shown side effects at the level of gallbladder and heart, hampering its clinical use ( 346 ).…”

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

“…Conformational changes resulting from methylation are well known in the chemistry community . In medicinal chemistry, the “magic” methyl concept has seen several successful examples ,,. Recently, methylation in late‐stage functionalization has been applied as a valuable tool in drug discovery .…”