Chapter 10. TGR5 Agonists in Development

Abstract

Lipid receptors are a growing family of druggable targets that include cell surface receptors and ligand-dependent transcription factors. 1 They mediate a plethora of signaling pathways involved in the fine tuning of important physiological functions such as the control of metabolism, organ physiology, cell differentiation, and homeostasis. As a consequence, small-molecule drug development for lipid receptors is attracting a great deal of interest in academia and pharmaceutical companies.TGR5, also known as M-BAR, AXOR109, BG37, or GPR131, is a membrane lipid receptor activated by bile acids (BAs) and G-protein coupled to the production of cAMP. The activation of TGR5 bestows on BAs the ability to modulate non-genomic signaling pathways that complement their genomic actions mostly mediated by the interaction with the nuclear receptor FXR. 2 Major non-genomic actions of BAs include immunosuppressive properties and the regulation of glucose metabolism as well as energy homeostasis. 3 While the therapeutic relevance of the immune properties of TGR5 activation is pending further appraisals, the effect of the receptor on glucose metabolism and energy homeostasis have thrust TGR5 into the limelight as an attractive therapeutic target in the arena of metabolic disorders, including type 2 diabetes (T2D) and obesity.

Recent Progress on Bile Acid Receptor Modulators for Treatment of Metabolic Diseases

“…This perspective review will highlight the most recent publications in the field of FXR modulators and provide a comprehensive literature summary of TGR5 agonists …”