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.
PEGylation of therapeutic agents
is known to improve the pharmacokinetic
behavior of macromolecular drugs and nanoparticles. In this work,
we performed the conjugation of polyethylene glycols (220–5000
Da) to a series of non-steroidal small agonists of the bile acids
receptor TGR5. A suitable anchoring position on the agonist was identified
to retain full agonistic potency with the conjugates. We describe
herein an extensive structure–properties relationships study
allowing us to finely describe the non-linear effects of the PEG length
on the physicochemical as well as the in vitro and in vivo pharmacokinetic properties of these compounds. When
appending a PEG of suitable length to the TGR5 pharmacophore, we were
able to identify either systemic or gut lumen-restricted TGR5 agonists.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.