Discovery of a new class of GPBAR1 modulators

Since the discovery of the G-protein-coupled bile acid receptor GPBAR1 (also known as TGR5), there has been an increased interest to pharmacologically modulate this target involved in lipids and glucose metabolism disorders such as nonalcoholic steatohepatitis, hypercholesterolaemia, hypertriglyceridaemia, and type 2 diabetes mellitus (1,2). Most of our previous research programs were focused to explore the chemical space of the bile acids, the endogenous GPBAR1 ligands (3-7). However, the specificity of bile acid derivatives is not restricted to this receptor and their clinical use can undergo some limitations exerting a variety of pathophysiological and pharmacological activities (8). Thus, recently, our investigations have been shifted towards the development of GPBAR1 non-bile acid modulators, with the final aim of identifying privileged chemical scaffolds able to exert a fine-tuning modulation of this receptor. In this context, using a rational structure-based design and a multidisciplinary approach, we have developed a library of novel active GPBAR1 ligands, that might provide new opportunities in the treatment of several metabolic disorders.