Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5

doi:10.1016/j.bmcl.2010.08.014

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 19, 1 October 2010, Pages 5718-5721

https://doi.org/10.1016/j.bmcl.2010.08.014 Get rights and content

Abstract

Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes.

Graphical abstract

Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes.

Section snippets

Acknowledgments

We thank Robyn Rourick and Nahid Yazdani for determining plasma levels for PK parameters and Nicholas D. Smith for helpful comments.

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TGR5 is emerging as an important and promising target for the treatment of diabetes, obesity and other metabolic syndromes. A series of novel 1-benzyl-1H-imidazole-5-carboxamide derivatives was designed, synthesized and evaluated in vitro and in vivo. The most potent compounds 19d and 19e exhibited excellent agonistic activities against hTGR5, which was superior to those of the reference drugs INT-777 and LCA. In addition, compounds 19d and 19e exhibited good selectivity against FXR and presented significant glucose-lowering effects in vivo. Compound 19d could stimulate GLP-1 secretion by activating of TGR5.
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The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex enterohepatic bile acid cycling limits the exposure of some of these tissues to the receptor ligand. Profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist. Data from preclinical studies show promising effects of targeting TGR5 on outcomes such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus on the translation of preclinical studies into clinically applicable findings. Studies in rodents suggest an important role for Tgr5 in Glp-1 secretion, insulin sensitivity, and energy expenditure. However, evidence of effects on these processes from human studies is less convincing. Ultimately, safe and selective human TGR5 agonists are needed to test the therapeutic potential of TGR5.
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Synthesis and SAR of 2-aryl-3-aminomethylquinolines as agonists of the bile acid receptor TGR5

Abstract

Graphical abstract

Section snippets

Acknowledgments

Drug Disc. Today

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Hepatol.

Biochem. Biophys. Res. Commun.

EMBO J.

Nature

J. Endocrinol.

Biochem. J.

Biochem. Biophys. Res. Commun.

Science