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J Med Chem. 2017 May 25;60(10):4185-4211. doi: 10.1021/acs.jmedchem.6b01873. Epub 2017 May 5.

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

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Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France.
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France.
Univ. Artois , EA 2465 - Blood-Brain Barrier Laboratory (LBHE), F-62300 Lens, France.


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.

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