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Review

TGR5 agonists for diabetes treatment: a patent review and clinical advancements (2012-present)

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Pages 191-209 | Received 07 Jun 2021, Accepted 13 Oct 2021, Published online: 22 Dec 2021

References

  • Kolb H, Martin S. Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes. BMC Med. 2017;15(1):131–142.
  • IDF Diabetes Atlas Ninth Edition 2019 [cited 07 June 2021]. https://www.diabetesatlas.org/en/
  • Tuomilehto J, Schwarz P, Lindstrom LJ. Long-term benefits from lifestyle interventions for type 2 diabetes prevention: time to expand the efforts. Diabetes Care. 2011;34(Supplement_2):S210–S214 .
  • Colberg R, Sigal J, Fernhall B, et al. Exercise and Type 2 Diabetes: the American college of sports medicine and the American diabetes association: joint position statement. Diabetes Care. 2010;33(12):147–167.
  • Bailey C, Tahrani A, Barnett A. Future glucose-lowering drugs for type 2 diabetes. Lancet Diabetes Endocrinol. 2016;4(4):350–359.
  • Gallwitz B. Clinical Use of DPP-4 Inhibitors. Frontiers in Endocrinology. 2019;10:1–10.
  • Hinnen D. Glucagon-like peptide 1 receptor agonists for type 2 diabetes. Diabetes Spectr. 2017;30(3):202–210.
  • Marín J, Timón I, Collantes C, et al. Update on the treatment of type 2 diabetes mellitus. World J Diabetes. 2016;7(17):354–395.
  • Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun. 2005;329(1):386–390.
  • Thomas C, Pellicciari R, Pruzanski M. Targeting bile-acid signaling for metabolic diseases. Nat Rev Drug Discovery. 2008;7(8):678–693.
  • Forman M, Goode E, Chen J, et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell. 1995;81(5):687–693.
  • Zhang Y, Woelbern R, Edwards A. natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. Journal of Biological Chemistry. 2003;278(1):104–110.
  • Wang D, Chen D, Moore D, et al. FXR: a metabolic regulator and cell protector. Cell Res. 2008;18(11):1087–1095.
  • Maruyama T, Tanaka K, Suzuki J, et al. Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J Endocrinol. 2006;191(1):197–205.
  • Kawamata, Kawamata Y, Fujii R, et al. A G Protein-coupled Receptor Responsive to Bile Acids. Journal of Biological Chemistry. 2003;278(11):9435–9440.
  • Thomas C, Gioiello A, Noriega L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metabolism. 2009;10(3):167–177.
  • Tang C, Chan L, Hsiao Y. TGR5 as new target in diabetes care. Curre. Res. Diabetes & Obes. J. 2018;9:555–759.
  • Stepanov V, Stankov K, Mikov M. The bile acid membrane receptor TGR5: a novel pharmacological target in metabolic, inflammatory and neoplastic disorders. Journal of Receptors and Signal Transduction. 2013;33(4):213–223.
  • Eggink H, Soeters M, Pols T. TGR5 ligands as potential therapeutics in inflammatory diseases. Int. J. Interf. Cyto. Med. Res. 2014;6:27–38.
  • Hodge R, Nunez D. Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype? Hope or Hype? Diabetes, Obesity and Metabolism. 2016;18(5):439–443.
  • Vettorazzi J, Ribeiro R, Borck P, et al. The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells. Metabolism. 2016;65(3):54–63.
  • Watanabe M, Houten S, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439(7075):484–489.
  • Pellicciari R, Sato H, Gioiello A, et al. Nongenomic Actions of Bile Acids. Synthesis and Preliminary Characterization of 23- and 6,23-Alkyl-Substituted Bile Acid Derivatives as Selective Modulators for the G-Protein Coupled Receptor TGR5. Journal of Medicinal Chemistry. 2007;50(18):4265–4268.
  • 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. Journal of Medicinal Chemistry. 52(24): 7958–7961. 2009.
  • Intercept Pharmaceuticals. TGR5 modulators and methods of use thereof . 2012;. United States Patent US8114862B2
  • Intercept Pharmaceuticals. TGR5 modulators and methods of use thereof. 2015;. United States patent US8999964B2
  • Intercept Pharmaceuticals. TGR5 modulators and methods of use thereof. 2016;. United States patent US9243027B2
  • BAR Pharmaceutica. Cholane derivative for use in the treatment and/or prevention of FXR/TGR5 mediated diseases. 2017;. United States Patent US2017/0190731A1
  • Enanta Pharmaceutica. Benzoic acid derivative of bile acids as FXR/TGR5 agonist and method of use thereof. 2019;. United States Patent US10323060B2
  • Enanta Pharmaceutica. Bile acids derivatives as FXR/TGR5 agonist and method of use thereof. 2019;. United States Patent US10208081B2
  • Enanta Pharmaceutica. Heteroaryl containing bile acids analogs as FXR/TGR5 agonist and method of use thereof. 2019;. United States Patent US10323061B2
  • Enanta Pharmaceutica. Process for the preparation of sulphonylurea bile acid derivatives. 2020;. United States Patent US10584145B2
  • Enanta Pharmaceutica. Process for the preparation of sulfonyl carbamate bile acid derivatives. 2020;. United States Patent US10676500B2
  • Takeda Pharmaceuticals. 2004; World Intellectual Property Organization WO043468A1
  • Cadila Healthcare Limited. Novel compounds for the treatment of diabetes, obesity, or related disorders. (2013) World Intellectual Property Organization WO2013102929A1
  • Cadila Healthcare Limited. Heterocyclic compounds and their use for the treatment of diabetes, obesity, or related disorders. 2013;. World Intellectual Property Organization WO2013164838A1
  • Exelixis, Inc. TGR5 agonists having an imidazole or triazole core with a substituent having quaternary nitrogen. 2014;. World Intellectual Property Organization WO2014100025A1
  • Janssen Pharmaceutica. Bicyclic pyrrole derivatives useful as agonists of GPR120. 2014;). Australian patent AU2014237600B2
  • Pharmaceutica J. Tetrahydro-benzo imidazolyl modulators of TGR5. 2015;. World Intellectual Property Organization WO2015160772A1
  • Ardelyx Inc. Substituted 4 phenyl pyridine compounds as non-systemic TGR5 agonists. 2017;. United States Patent US20170174718A1
  • Charton J, Deprez B, Leroux F, Staels B, Muhr-tailleux A, Hennuyer N, Lestavel S, Picon S, Aknin K, Boulahjar R, Dubanchet B, 2-Oxo-3,4-dihydropyridine–5 carboxylates and their use. 2018; United States PatentUS9932309B2
  • Charton J, Deprez B, Leroux F, Staels B, Muhr-tailleux A, Hennuyer N, Lestavel S, Lassalle M, Dubanchet B, et al. Imidazole or 1,2,4 triazole derivatives and their use. 2019; United States patent US10323016B2
  • Merck Corp. Antidiabetic bicyclic compounds . 2020;. United States patent US10662171B2
  • Qui Q. 5,5 dimethylcyclohexylene derivatives and their applications in metabolic diseases . (2020). Chinese patent CN111303067A
  • Quzhen Q. Thiazole diamino derivatives and their use in metabolic diseases Chinese patentCN111440162A (2020).
  • Weidong C, Zaho S, Wang Y, Ye W, Nie X, Zhou Y, LI X Phenylethyl derivatives and their use. 2020;. Chinese Patent CN111763173A
  • ClinicalTrials.gov: NCT00607906 A Single-blinded, Randomized, Placebo-controlled, Staggered-parallel, Escalating Single Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orally Administered SB756050 in Healthy Volunteers and Subjects with Type 2 Diabetes Mellitus [cited 07 June 2021]. Available from: https://clinicaltrials.gov/ct2/show/NCT00607906?term=NCT00607906&draw=2&rank=1
  • Hodge R, Lin J, Vasist L, et al. Safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB−756050, in type 2 diabetes. Clin. Pharmacol. Drug Dev. 2013;2:213–222.
  • Clinicaltrials.gov: NCT01337440. Efficacy and safety of Ursodeoxycholic Acid (UDCA) added to DPPIV inhibitor in people with Type 2 diabetes and chronic liver diseases [cited 07 June 2021]. Available from: https://clinicaltrials.gov/ct2/show/NCT01337440?term=GPR131&draw=2&rank=1
  • Robert S,1, Tsuguhito O,1, Ken-ichiro K, et al. Ursodeoxycholic acid potentiates dipeptidyl peptidase-4 inhibitor sitagliptin by enhancing glucagon-like peptide-1 secretion in patients with type 2 diabetes and chronic liver disease: a pilot randomized controlled and addon study. BMJ Open Diab Res Care. 2018;6. 469.
  • Clinicaltrials.gov: NCT01674946. Effect of bile acids on the secretion of satiation peptides in humans [cited 07 June 2021]. Available from: https://clinicaltrials.gov/ct2/show/NCT01674946?term=TGR5&draw=1&rank=1
  • Meyer C, Steinert R, Keller S, et al. Effects of Chenodeoxycholic Acid on the Secretion of Gut Peptides and Fibroblast Growth Factors in Healthy Humans. The Journal of Clinical Endocrinology & Metabolism. 2013;98(8):3351–3358.
  • Chen G, Wang X, Ge Y, et al. Cryo-EM structure of activated bile acids receptor TGR5 in complex with stimulatory G protein. Signal Transduction and Targeted Therapy. 2020;5(1): 142-142. https://doi.org/10.1038/s41392-020-00262-z.
  • Yang F, Mao C, Guo L, et al., Structural basis of GPBAR activation and bile acid recognition. Nature. 587(7834): 499–504. 2020.
  • Keitel V, Haussinger D. Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clinics and Research in Hepatology and Gastroenterology. 2012;36(5):412–419.
  • Keitel V, Gorg B, Bidmon H, et al. The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain. Glia. 2010;58(15):1794–1805.
  • Fiorucci S, Mencarelli A, Palladino G, et al. Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders. Trends Pharmacol Sci. 2009;30(11):570–580.
  • Keitel V, Reinehr R, Gatsios P, et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology. 2007;45(3):695–704.
  • Keitel V, Donner M, Winandy S, et al. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun. 2008;372(1):78–84.
  • Li T, Holmstrom SR, Kir S, et al., The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol Endocrinol. 25(6): 1066–1071. 2011.
  • Lavoie B, Balemba OB, Godfrey C, et al. Hydrophobic bile salts inhibit gallbladder smooth muscle function via stimulation of GPBAR1 receptors and activation of K ATP channels. J Physiol. 2010;588(17):295–305.
  • Cao H, Chen Z, Wang K, et al. Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect. Sci Rep. 2016;6(1):28676.
  • Duan H, Ning M, Zou Q, et al. Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes. Journal of Medicinal Chemistry. 2015;58(8):3315–3328.
  • Ma Y, Nin M, Zou A, et al. OL3, a novel low-absorbed TGR5 agonist with reduced side effects, lowered blood glucose via dual actions on TGR5 activation and DPP-4 inhibition. Acta Pharmacol Sin. 2016;37(10):1359.
  • Filipski J, Varma V, Kattan F, et al. Intestinal targeting of drugs: rational design approaches and challenges. Current Topics in Medicinal Chemistry. 2013; 13(7) 776–802.

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