INT-777

INT-777 is a semisynthetic bile acid that acts as an agonist of TGR5 (EC₅₀ = 0.82 µM).^1,2 It is active in vivo, stimulating the secretion of glucagon-like peptide 1 (GLP-1) in mice when given orally (30 mg/kg) after a glucose challenge, particularly when given with a dipeptidyl-peptidase-4 inhibitor.² INT-777 increases energy expenditure and reduces hepatic steatosis and adiposity in mice subjected to diet-induced obesity.² It also stimulates insulin secretion in pancreatic β-cells, reduces inflammation and inhibits atherosclerosis in mice, and promotes chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) in Calu-3 airway epithelial cells.^3,4,5

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1. Pellicciari, R., Gioiello, A., Macchiarulo, A., et al. Discovery of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity. J. Med. Chem. 52(24), 7958-7961 (2009).

2. Thomas, C., Gioiello, A., Noriega, L., et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10(3), 167-177 (2009).

3. Kumar, D.P., Rajagopal, S., Mahavadi, S., et al. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic ß cells. Biochem. Biophys. Res. Commun. 427(3), 600-605 (2012).

4. Pols, T.W.H., Nomura, M., Harach, T., et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. 14(6), 747-757 (2011).

5. Hendrick, S.M., Mroz, M.S., Greene, C.M., et al. Bile acids stimulate chloride secretion through CFTR and calcium-activated Cl- channels in Calu-3 airway epithelial cells. Am. J. Physiol. Lung. Cell. Mol. Physiol. 307(5), L407-L418 (2014).