GPR119 agonists for type 2 diabetes: past failures and future hopes for preclinical and early phase candidates

References

• Padhi S, Nayak AK, Behera A. Type II diabetes mellitus: a review on recent drug based therapeutics. Biomed Pharmacother. 2020 Nov;131:110708. doi: 10.1016/j.biopha.2020.110708
   PubMed Web of Science ®Google Scholar
• Bellou V, Belbasis L, Tzoulaki I, et al. Risk factors for type 2 diabetes mellitus: an exposure-wide umbrella review of meta-analyses. PLoS One. 2018;13(3):e0194127. doi: 10.1371/journal.pone.0194127
   PubMed Web of Science ®Google Scholar
• Ke C, Narayan KMV, Chan JCN, et al. Pathophysiology, phenotypes and management of type 2 diabetes mellitus in Indian and Chinese populations. Nat Rev Endocrinol. 2022;18(7):413–432. doi: 10.1038/s41574-022-00669-4
   PubMed Web of Science ®Google Scholar
• Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus–present and future perspectives. Nat Rev Endocrinol. 2011 Nov 8;8(4):228–236.
   PubMed Web of Science ®Google Scholar
• Yan Y, Wu T, Zhang M, et al. Prevalence, awareness and control of type 2 diabetes mellitus and risk factors in Chinese elderly population. BMC Public Health. 2022;22(1):1382. doi: 10.1186/s12889-022-13759-9
   PubMed Web of Science ®Google Scholar
• Skyler JS. Diabetic complications. The importance of glucose control. Endocrinol Metab Clin North Am. 1996 Jun;25(2):243–254. doi: 10.1016/S0889-8529(05)70323-6
   PubMed Web of Science ®Google Scholar
• Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK prospective diabetes study (UKPDS) group. Lancet. 1998 Sep 12;352(9131):854–865. doi: 10.1016/S0140-6736(98)07037-8
   PubMed Web of Science ®Google Scholar
• Zanuso S, Jimenez A, Pugliese G, et al. Exercise for the management of type 2 diabetes: a review of the evidence. Acta Diabetol. 2010 Mar;47(1):15–22.
   PubMed Web of Science ®Google Scholar
• Manaithiya A, Alam O, Sharma V, et al. GPR119 agonists: novel therapeutic agents for type 2 diabetes mellitus. Bioorg Chem. 2021 Aug;113:104998.
   PubMed Web of Science ®Google Scholar
• Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American diabetes Association (ADA) and the European Association for the Study of diabetes (EASD). Diabetologia. 2022 Dec;65(12):1925–1966.
   PubMed Web of Science ®Google Scholar
• Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. 2016 Jul 19;316(3):313–324. doi: 10.1001/jama.2016.9400
   PubMed Web of Science ®Google Scholar
• Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: a systematic review and network meta-analysis. Ann Intern Med. 2020 Aug 18;173(4):278–286. doi: 10.7326/M20-0864
   PubMed Web of Science ®Google Scholar
• Chu ZL, Carroll C, Alfonso J, et al. A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release. Endocrinology. 2008 May;149(5):2038–2047.
   PubMed Web of Science ®Google Scholar
• Fredriksson R, Höglund PJ, Gloriam DE, et al. Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives. FEBS Lett. 2003 Nov 20;554(3):381–388. doi: 10.1016/S0014-5793(03)01196-7
   PubMed Web of Science ®Google Scholar
• Irving A, Abdulrazzaq G, Chan SLF, et al. Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors. Adv Pharmacol. 2017;80:223–247.
   PubMedGoogle Scholar
• Chu ZL, Jones RM, He H, et al. A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology. 2007 Jun;148(6):2601–2609.
   PubMed Web of Science ®Google Scholar
• Drucker DJ, Jin T, Asa SL, et al. Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line. Mol Endocrinol. 1994 Dec;8(12):1646–1655.
   PubMedGoogle Scholar
• Cornall LM, Mathai ML, Hryciw DH, et al. GPR119 regulates genetic markers of fatty acid oxidation in cultured skeletal muscle myotubes. Mol Cell Endocrinol. 2013 Jan 5;365(1):108–18. doi: 10.1016/j.mce.2012.10.003
   PubMed Web of Science ®Google Scholar
• Cornall LM, Hryciw DH, Mathai ML, et al. Direct activation of the proposed anti-diabetic receptor, GPR119 in cardiomyoblasts decreases markers of muscle metabolic activity. Mol Cell Endocrinol. 2015 Feb 15;402:72–85.
   PubMed Web of Science ®Google Scholar
• Michel MC, Wieland T, Tsujimoto G. How reliable are G-protein-coupled receptor antibodies? Naunyn Schmiedebergs Arch Pharmacol. 2009 Apr;379(4):385–388. doi: 10.1007/s00210-009-0395-y
   PubMed Web of Science ®Google Scholar
• Qian Y, Wang J, Yang L, et al. Activation and signaling mechanism revealed by GPR119-gs complex structures. Nat Commun. 2022;13(1):7033. doi: 10.1038/s41467-022-34696-6
   PubMed Web of Science ®Google Scholar
• Xu P, Huang S, Guo S, et al. Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119. Nat Struct Mol Biol. 2022 Sep;29(9):863–870.
   PubMed Web of Science ®Google Scholar
• Soga T, Ohishi T, Matsui T, et al. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem Biophys Res Commun. 2005 Jan 28;326(4):744–751. doi: 10.1016/j.bbrc.2004.11.120
   PubMed Web of Science ®Google Scholar
• Overton HA, Babbs AJ, Doel SM, et al. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 2006 Mar;3(3):167–175.
   PubMed Web of Science ®Google Scholar
• Lo Verme J, Gaetani S, Fu J, et al. Regulation of food intake by oleoylethanolamide. Cell Mol Life Sci. 2005 Mar;62(6):708–716.
   PubMed Web of Science ®Google Scholar
• Proulx K, Cota D, Castañeda TR, et al. Mechanisms of oleoylethanolamide-induced changes in feeding behavior and motor activity. Am J Physiol Regul Integr Comp Physiol. 2005 Sep;289(3):R729–37.
   PubMed Web of Science ®Google Scholar
• Overton HA, Fyfe MC, Reynet C. GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br J Pharmacol. 2008 Mar;153(Suppl 1):S76–81. doi: 10.1038/sj.bjp.0707529
   PubMed Web of Science ®Google Scholar
• Yang JW, Kim HS, Choi YW, et al. Therapeutic application of GPR119 ligands in metabolic disorders. Diab Obes Metab. 2018 Feb;20(2):257–269.
   PubMed Web of Science ®Google Scholar
• Meier JJ, Gallwitz B, Schmidt WE, et al. Glucagon-like peptide 1 as a regulator of food intake and body weight: therapeutic perspectives. Eur J Pharmacol. 2002 Apr 12;440(2–3):269–279. doi: 10.1016/S0014-2999(02)01434-6
   PubMed Web of Science ®Google Scholar
• Buzard DJ, Kim SH, Lehmann J, et al. Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists. Bioorg Med Chem Lett. 2014 Sep 1;24(17):4332–4335. doi: 10.1016/j.bmcl.2014.06.071
   PubMed Web of Science ®Google Scholar
• Semple G, Lehmann J, Wong A, et al. Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1750–1755. doi: 10.1016/j.bmcl.2011.12.092
   PubMed Web of Science ®Google Scholar
• Semple G, Ren A, Fioravanti B, et al. Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control. Bioorg Med Chem Lett. 2011 May 15;21(10):3134–3141. doi: 10.1016/j.bmcl.2011.03.007
   PubMed Web of Science ®Google Scholar
• Bahirat UA, Talwar R, Shenoy RR, et al. Combination of APD668, a G protein-coupled receptor 119 agonist with linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in a murine model of non-alcoholic steatohepatitis with diabetes. Med Mol Morphol. 2019 Mar;52(1):36–43.
   PubMed Web of Science ®Google Scholar
• Bahirat UA, Shenoy RR, Talwar R, et al. Co-administration of APD668, a G protein-coupled receptor 119 agonist and linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in mice fed on a high trans-fat diet. Biochem Biophys Res Commun. 2018 Jan 8;495(2):1608–1613. doi: 10.1016/j.bbrc.2017.12.004
   PubMed Web of Science ®Google Scholar
• Yoshida S, Ohishi T, Matsui T, et al. Identification of a novel GPR119 agonist, AS1269574, with in vitro and in vivo glucose-stimulated insulin secretion. Biochem Biophys Res Commun. 2010 Sep 24;400(3):437–441. doi: 10.1016/j.bbrc.2010.08.097
   PubMed Web of Science ®Google Scholar
• McKillop AM, Moran BM, Abdel-Wahab YH, et al. Metabolic effects of orally administered small-molecule agonists of GPR55 and GPR119 in multiple low-dose streptozotocin-induced diabetic and incretin-receptor-knockout mice. Diabetologia. 2016 Dec;59(12):2674–2685.
   PubMed Web of Science ®Google Scholar
• Yoshida S, Ohishi T, Matsui T, et al. Novel GPR119 agonist AS1535907 contributes to first-phase insulin secretion in rat perfused pancreas and diabetic db/db mice. Biochem Biophys Res Commun. 2010 Nov 12;402(2):280–5. doi: 10.1016/j.bbrc.2010.10.015
   PubMed Web of Science ®Google Scholar
• Yoshida S, Ohishi T, Matsui T, et al. The role of small molecule GPR119 agonist, AS1535907, in glucose-stimulated insulin secretion and pancreatic β-cell function. Diab Obes Metab. 2011 Jan;13(1):34–41.
   PubMed Web of Science ®Google Scholar
• Ritter K, Buning C, Halland N, et al. G protein-coupled receptor 119 (GPR119) agonists for the treatment of diabetes: recent progress and prevailing challenges. J Med Chem. 2016 Apr 28;59(8):3579–3592. doi: 10.1021/acs.jmedchem.5b01198
   PubMed Web of Science ®Google Scholar
• Oshima H, Yoshida S, Ohishi T, et al. Novel GPR119 agonist AS1669058 potentiates insulin secretion from rat islets and has potent anti-diabetic effects in ICR and diabetic db/db mice. Life Sci. 2013 Feb 7;92(2):167–173. doi: 10.1016/j.lfs.2012.11.015
   PubMed Web of Science ®Google Scholar
• Yoshida S, Tanaka H, Oshima H, et al. AS1907417, a novel GPR119 agonist, as an insulinotropic and β-cell preservative agent for the treatment of type 2 diabetes. Biochem Biophys Res Commun. 2010 Oct 1;400(4):745–751. doi: 10.1016/j.bbrc.2010.08.141
   PubMed Web of Science ®Google Scholar
• Wacker DA, Wang Y, Broekema M, et al. Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119. J Med Chem. 2014 Sep 25;57(18):7499–508. doi: 10.1021/jm501175v
   PubMed Web of Science ®Google Scholar
• Kim MK, Cheong YH, Lee SH, et al. A novel GPR119 agonist DA-1241 preserves pancreatic function via the suppression of ER stress and increased PDX1 expression. Biomed Pharmacother. 2021 Dec;144:112324.
   PubMed Web of Science ®Google Scholar
• Kim Y, Lee SW, Wang H, et al. DA-1241, a Novel GPR119 Agonist, improves hyperglycaemia by inhibiting hepatic gluconeogenesis and enhancing insulin secretion in diabetic mice. Diabetes Metab J. 2022 Mar;46(2):337–348.
   PubMed Web of Science ®Google Scholar
• Murakami T, Fujimoto H, Fujita N, et al. Noninvasive evaluation of GPR119 agonist effects on β-Cell Mass in Diabetic Male Mice Using 111In-exendin-4 SPECT/CT. Endocrinology. 2019 Dec 1;160(12):2959–2968. doi: 10.1210/en.2019-00556
   PubMed Web of Science ®Google Scholar
• Matsumoto K, Yoshitomi T, Ishimoto Y, et al. DS-8500a, an Orally Available G Protein-Coupled Receptor 119 Agonist, Upregulates Glucagon-Like Peptide-1 and Enhances Glucose-Dependent Insulin Secretion and Improves Glucose Homeostasis in Type 2 Diabetic Rats. J Pharmacol Exp Ther. 2018 Dec;367(3):509–517.
   PubMed Web of Science ®Google Scholar
• Ahlkvist L, Brown K, Ahrén B. Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion. Endocr Connect. 2013 Jun 1;2(2):69–78.
   PubMed Web of Science ®Google Scholar
• Al-Barazanji K, McNulty J, Binz J, et al. Synergistic effects of a GPR119 agonist with Metformin on weight loss in diet-induced obese mice. J Pharmacol Exp Ther. 2015 Jun;353(3):496–504.
   PubMed Web of Science ®Google Scholar
• Huan Y, Jiang Q, Li G, et al. The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo. Sci Rep. 2017 Jun 28;7(1):4351. doi: 10.1038/s41598-017-04633-5
   PubMedGoogle Scholar
• Ha TY, Kim YS, Kim CH, et al. Novel GPR119 agonist HD0471042 attenuated type 2 diabetes mellitus. Arch Pharm Res. 2014 May;37(5):671–678.
   PubMed Web of Science ®Google Scholar
• Kim SR, Kim DH, Park SH, et al. In vivo efficacy of HD0471953: a novel GPR119 agonist for the treatment of type 2 diabetes mellitus. J Diabetes Res. 2013;2013:269569. doi: 10.1155/2013/269569
   PubMed Web of Science ®Google Scholar
• Kim S, Kim DH, Kim YS, et al. HD047703, a New Promising Anti-Diabetic Drug Candidate: In Vivo Preclinical Studies. Biomol Ther. 2014 Sep;22(5):400–405.
   PubMed Web of Science ®Google Scholar
• Tadaki H, Sasase T, Fukuda S, et al. Chronic treatment of JTP-109192, a novel G-protein coupled receptor 119 agonist, improves metabolic abnormalities in Zucker fatty rats. Clin Exp Pharmacol Physiol. 2019 Oct;46(10):910–919.
   PubMed Web of Science ®Google Scholar
• Han T, Lee BM, Park YH, et al. YH18968, a novel 1,2,4-triazolone G-Protein coupled receptor 119 agonist for the treatment of type 2 diabetes mellitus. Biomol Ther. 2018 Mar 1;26(2):201–209. doi: 10.4062/biomolther.2018.011
   PubMed Web of Science ®Google Scholar
• Yang JW, Kim HS, Im JH, et al. GPR119: a promising target for nonalcoholic fatty liver disease. FASEB J. 2016 Jan;30(1):324–35.
   PubMed Web of Science ®Google Scholar
• Neelamkavil SF, Stamford AW, Kowalski T, et al. Discovery of MK-8282 as a potent G-Protein-coupled receptor 119 agonist for the treatment of type 2 diabetes. ACS Med Chem Lett. 2018 May 10;9(5):457–461. doi: 10.1021/acsmedchemlett.8b00073
   PubMed Web of Science ®Google Scholar
• Zhang M, Feng Y, Wang J, et al. High-throughput screening for GPR119 modulators identifies a novel compound with anti-diabetic efficacy in db/db mice. PLoS One. 2013;8(5):e63861. doi: 10.1371/journal.pone.0063861
   PubMed Web of Science ®Google Scholar
• Zhang SY, Li J, Xie X. Discovery and characterization of novel small molecule agonists of G protein-coupled receptor 119. Acta Pharmacol Sin. 2014 Apr;35(4):540–548. doi: 10.1038/aps.2014.8
   PubMed Web of Science ®Google Scholar
• Ansarullah LY, Holstein M, Holstein M, et al. Stimulating β-cell regeneration by combining a GPR119 agonist with a DPP-IV inhibitor. PLoS One. 2013;8(1):e53345. doi: 10.1371/journal.pone.0053345
   PubMed Web of Science ®Google Scholar
• Park YH, Choi HH, Lee DH, et al. YH18421, a novel GPR119 agonist exerts sustained glucose lowering and weight loss in diabetic mouse model. Arch Pharm Res. 2017 Jun;40(6):772–782.
   PubMed Web of Science ®Google Scholar
• Tyurenkov IN, Kurkin DV, Bakulin DA, et al. Chemistry and hypoglycemic activity of GPR119 agonist ZB-16. Front Endocrinol. 2018;9:543. doi: 10.3389/fendo.2018.00543
   PubMed Web of Science ®Google Scholar
• Tyurenkov IN, Kurkin DV, Bakulin DA, et al. ZB-16, a Novel GPR119 Agonist, relieves the severity of streptozotocin-nicotinamide-induced diabetes in rats. Front Endocrinol. 2017;8:152. doi: 10.3389/fendo.2017.00152
   PubMed Web of Science ®Google Scholar
• Pola S, Shah SR, Pingali H, et al. Discovery of a potent G-protein-coupled receptor 119 agonist for the treatment of type 2 diabetes. Bioorg Med Chem. 2021 Apr 1;35:116071.
   PubMed Web of Science ®Google Scholar
• Shah U, Kowalski TJ. GPR119 agonists for the potential treatment of type 2 diabetes and related metabolic disorders. Vitam Horm. 2010;84:415–448.
   PubMed Web of Science ®Google Scholar
• Semple G, Fioravanti B, Pereira G, et al. Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119. J Med Chem. 2008 Sep 11;51(17):5172–5175. doi: 10.1021/jm8006867
   PubMed Web of Science ®Google Scholar
• Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest. 2007 Jan;117(1):24–32. doi: 10.1172/JCI30076
   PubMed Web of Science ®Google Scholar
• Sun D, Gao W, Hu H, et al. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022 Jul;12(7):3049–3062.
   PubMed Web of Science ®Google Scholar
• McClure KF, Darout E, Guimarães CR, et al. Activation of the G-protein-coupled receptor 119: a conformation-based hypothesis for understanding agonist response. J Med Chem. 2011 Mar 24;54(6):1948–1952. doi: 10.1021/jm200003p
   PubMed Web of Science ®Google Scholar
• Katz LB, Gambale JJ, Rothenberg PL, et al. Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes. Diab Obes Metab. 2012 Aug;14(8):709–716.
   PubMed Web of Science ®Google Scholar
• Nunez DJ, Bush MA, Collins DA, et al. Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies. PLoS One. 2014;9(4):e92494. doi: 10.1371/journal.pone.0092494
   PubMed Web of Science ®Google Scholar
• Inagaki N, Chou HS, Tsukiyama S, et al. Glucose-lowering effects and safety of DS-8500a, a G protein-coupled receptor 119 agonist, in Japanese patients with type 2 diabetes: results of a randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase II study. BMJ Open Diabetes Res Care. 2017;5(1):e000424. doi: 10.1136/bmjdrc-2017-000424
   PubMed Web of Science ®Google Scholar
• Terauchi Y, Yamada Y, Watada H, et al. Efficacy and safety of the G protein-coupled receptor 119 agonist DS-8500a in Japanese type 2 diabetes mellitus patients with inadequate glycemic control on sitagliptin: a phase 2 randomized placebo-controlled study. J Diabetes Investig. 2018 Nov;9(6):1333–1341.
   PubMed Web of Science ®Google Scholar
• Yamada Y, Terauchi Y, Watada H, et al. Efficacy and Safety of GPR119 Agonist DS-8500a in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Adv Ther. 2018 Mar;35(3):367–381.
   PubMed Web of Science ®Google Scholar
• Watada H, Shiramoto M, Irie S, et al. G protein-coupled receptor 119 agonist DS-8500a effects on pancreatic β-cells in Japanese type 2 diabetes mellitus patients. J Diabetes Investig. 2019 Jan;10(1):84–93.
   PubMed Web of Science ®Google Scholar
• Kang SU. GPR119 agonists: a promising approach for T2DM treatment? A SWOT analysis of GPR119. Drug Discov Today. 2013 Dec;18(23–24):1309–1315. doi: 10.1016/j.drudis.2013.09.011
   PubMed Web of Science ®Google Scholar
• Kautzky-Willer A, Leutner M, Harreiter J. Sex differences in type 2 diabetes. Diabetologia. 2023 Jun;66(6):986–1002. doi: 10.1007/s00125-023-05891-x
   PubMed Web of Science ®Google Scholar
• Miller S, Hu SS, Leishman E, et al. A GPR119 signaling system in the murine eye regulates intraocular pressure in a sex-dependent manner. Invest Ophthalmol Vis Sci. 2017 Jun 1;58(7):2930–2938. doi: 10.1167/iovs.16-21330
   PubMed Web of Science ®Google Scholar
• Hodge D, Glass LL, Diakogiannaki E, et al. Lipid derivatives activate GPR119 and trigger GLP-1 secretion in primary murine L-cells. Peptides. 2016 Mar;77:16–20.
   PubMed Web of Science ®Google Scholar
• Franconi F, Brunelleschi S, Steardo L, et al. Gender differences in drug responses. Pharmacol Res. 2007 Feb;55(2):81–95.
   PubMed Web of Science ®Google Scholar
• Caruso I, Di Gioia L, Di Molfetta S, et al. Glucometabolic outcomes of GLP-1 receptor agonist-based therapies in patients with type 2 diabetes: a systematic review and network meta-analysis. EClinicalMedicine. 2023 Oct;64:102181.
   PubMedGoogle Scholar