INT-777

INT-777 (S-EMCA) is a potent and selective agonist of TGR5 receptor with EC50 value of 0.82 μM [1].

TGR5 receptor is a G protein-coupled receptor and functions as a cell surface receptor for bile acids. TGR5 receptor plays an important role in the regulation of energy homeostasis by bile acids and suppression of macrophage functions [1].

INT-777 (S-EMCA) is a potent and selective TGR5 receptor agonist [1]. In macrophages, INT-777 inhibited proinflammatory cytokine production by TGR5-induced cAMP signaling and subsequent NF-kB inhibition [2]. In pancreatic β cell line MIN6, INT-777 selectively activated Gαs and increased intracellular cAMP and Ca2+. INT-777 also increased phosphoinositide (PI) hydrolysis and insulin release, which was dependent on Gs/cAMP/Ca2+ pathway [3]. In human podocytes with high glucose, INT-777 induced mitochondrial biogenesis, increased fatty acid β-oxidation and decreased oxidative stress [4].

In Ldlr- /- Tgr5+/+ mice, INT-777 activated TGR5 and attenuated atherosclerosis, which was associated with less plaque macrophage content and decreased intraplaque inflammation [2]. In diabetic db/db mice, INT-777 decreased mitochondrial H2O2 production and increased SOD2 activity, then reduced proteinuria, mesangial expansion, podocyte injury, fibrosis, and CD68 macrophage infiltration in the kidney [4].

References:
[1].  Pellicciari R, Gioiello A, Macchiarulo A, et al. Discovery of 6alpha-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, 2009, 52(24): 7958-7961.
[2].  Pols TW, Nomura M, Harach T, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab, 2011, 14(6): 747-757.
[3].  Kumar DP, Rajagopal S, Mahavadi S, et al. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells. Biochem Biophys Res Commun, 2012, 427(3): 600-605.
[4].  Wang XX, Edelstein MH, Gafter U, et al. G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes. J Am Soc Nephrol, 2015. pii: ASN.2014121271.

Reduction of epithelial secretion in male rat distal colonic mucosa by bile acid receptor TGR5 agonist, INT-777: role of submucosal neurons.[Pubmed:27259385]

Neurogastroenterol Motil. 2016 Nov;28(11):1663-1676.

BACKGROUND: Recent evidence from rat neuron-free mucosa study suggests that the membrane bile acid receptor TGR5 decreases colonic secretion under basal and stimulated conditions. As submucosal neurons are key players in secretory processes and highly express TGR5, we investigated their role in TGR5 agonist-induced inhibition of secretion and the pathways recruited. METHODS: TGR5 expression and localization were assessed in rat proximal (pC) and distal (dC) colon by qPCR and immunohistochemistry with double labeling for cholinergic neurons in whole-mount preparations. The influence of a selective (INT-777) or weak (ursodeoxycholic acid, UDCA) TGR5 agonist on colonic secretion was assessed in Ussing chambers, in dC preparation removing seromuscular +/- submucosal tissues, in the presence of different inhibitors of secretion pathways. KEY RESULTS: TGR5 mRNA is expressed in full thickness dC and pC and immunoreactivity is located in colonocytes and pChAT-positive neurons. Addition of INT-777, and less potently UDCA, decreased colonic secretion in seromuscular stripped dC by -58.17+/- 2.6%. INT-777 effect on basal secretion was reduced in neuron-free and TTX-treated mucosal-submucosal preparations. Atropine, hexamethonium, indomethacin, and L-NAME all reduced significantly INT-777's inhibitory effect while the 5-HT4 antagonist, RS-39604, and lidocaine abolished it. INT-777 inhibited stimulated colonic secretion induced by nicotine, but not cisapride, carbachol or PGE2. CONCLUSIONS & INFERENCES: TGR5 activation inhibits basal and stimulated distal colonic secretion in rats by acting directly on epithelial cells and also inhibiting submucosal neurons. This could represent a counter-regulatory mechanism, at the submucosal level, of the known prosecretory effect of bile acids in the colon.

Discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity.[Pubmed:20014870]

J Med Chem. 2009 Dec 24;52(24):7958-61.

In the framework of the design and development of TGR5 agonists, we reported that the introduction of a C(23)(S)-methyl group in the side chain of bile acids such as chenodeoxycholic acid (CDCA) and 6-ethylchenodeoxycholic acid (6-ECDCA, INT-747) affords selectivity for TGR5. Herein we report further lead optimization efforts that have led to the discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a novel potent and selective TGR5 agonist with remarkable in vivo activity.