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YH18421, a novel GPR119 agonist exerts sustained glucose lowering and weight loss in diabetic mouse model

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Abstract

G-protein-coupled receptor 119 (GPR119) represents a promising target for the treatment of type 2 diabetes as it can increase both GLP-1 secretion from intestinal L cells and glucose-stimulated insulin secretion (GSIS) from pancreatic β cells. Due to this dual mechanism of action, the development of small molecule GPR119 agonists has received much interest for the treatment of type 2 diabetes. Here, we identified a novel small-molecule GPR119 agonist, YH18421 and evaluated its therapeutic potential. YH18421 specifically activated human GPR119 with high potency and potentiated GLP-1 secretion and GSIS in vitro cell based systems. In normal mice, single oral administration of YH18421 improved glucose tolerance. Combined treatment of YH18421 and the DPP-4 inhibitor augmented both plasma active GLP-1 levels and glycemic control. In diet induced obese (DIO) mice model, glucose lowering effect of YH18421 was maintained after 4 weeks of repeat dosing and YH18421 acted additively with DPP-IV inhibitor. We also observed that YH18421 inhibited weight gain during 4 weeks of administration in DIO mice. These data demonstrate that YH18421 is capable of delivering sustained glucose control and preventing weight gain and combination with the DPP-IV inhibitor maybe an effective strategy for the treatment of type 2 diabetes.

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References

  • Al-Barazanji K, McNulty J, Binz J, Generaux C, Benson W, Young A, Chen L (2015) Synergistic effects of a GPR119 agonist with metformin on weight loss in diet-induced obese mice. J Pharmacol Exp Ther 353:496–504

    Article  CAS  PubMed  Google Scholar 

  • American Diabetes Association (2014) Standards of medical care in diabetes. Diabetes Care 37(Suppl 1):S14–S80

    Article  Google Scholar 

  • Bahirat UA, Shenoy RR, Goel RN, Nemmani KV (2017) APD668, a G protein-coupled receptor 119 agonist improves fat tolerance and attenuates fatty liver in high-trans fat diet induced steatohepatitis model in C57BL/6 mice. Eur J Pharmacol 801:35–45

    Article  CAS  PubMed  Google Scholar 

  • Chu ZL, Jones RM, He H, Carroll C, Gutierrez V, Lucman A, Moloney M, Gao H, Mondala H, Bagnol D, Unett D, Liang Y, Demarest K, Semple G, Behan DP, Leonard J (2007) A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology 148:2601–2609

    Article  CAS  PubMed  Google Scholar 

  • Chu ZL, Carroll C, Alfonso J, Gutierrez V, He H, Lucman A, Pedraza M, Mondala H, Gao H, Bagnol D, Chen R, Jones RM, Behan DP, Leonard J (2008) 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 149:2038–2047

    Article  CAS  PubMed  Google Scholar 

  • Chu ZL, Carroll C, Chen R, Alfonso J, Gutierrez V, He H, Lucman A, Xing C, Sebring K, Zhou J, Wagner B, Unett D, Jones RM, Behan DP, Leonard J (2010) N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119. Mol Endocrinol 24:161–170

    Article  PubMed  PubMed Central  Google Scholar 

  • Cornall LM, Mathai ML, Hryciw DH, Simcocks AC, O’Brien PE, Wentworth JM, McAinch AJ (2013) GPR119 regulates genetic markers of fatty acid oxidation in cultured skeletal muscle myotubes. Mol Cell Endocrinol 365:108–118

    Article  CAS  PubMed  Google Scholar 

  • Cornall LM, Hryciw DH, Mathai ML, McAinch AJ (2015) Direct activation of the proposed anti-diabetic receptor, GPR119 in cardiomyoblasts decreases markers of muscle metabolic activity. Mol Cell Endocrinol 402:72–85

    Article  CAS  PubMed  Google Scholar 

  • DeFronzo RA, Bonadonna RC, Ferrannini E (1999) Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15:318–368

    Article  Google Scholar 

  • Drucker DJ (1998) Glucagon-like peptide. Diabetes 47:159–169

    Article  CAS  PubMed  Google Scholar 

  • Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368:1696–1705

    Article  CAS  PubMed  Google Scholar 

  • Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Eng J Med 341:879–884

    Article  CAS  Google Scholar 

  • Fowler Michael J (2007) Diabetes treatment, Part 2: oral agents for glycemic management. Clin Diabetes 25:131–134

    Article  Google Scholar 

  • Fredriksson R, Hoglund PJ, Gloriam DE, Lagerstrom MC, Schioth HB (2003) Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives. FEBS Lett 554:381–388

    Article  CAS  PubMed  Google Scholar 

  • Ha TY, Kim YS, Kim CH, Choi HS, Yang J, Park SH, Kim DH, Rhee JK (2014) Novel GPR119 agonist HD0471042 attenuated type 2 diabetes mellitus. Arch Pharm Res 37:671–678

    Article  CAS  PubMed  Google Scholar 

  • Jay BF (2012) ARRY-981, a GPR119 agonist for the treatment of T2DM. Discovery on target 2012

  • Jones RM, Leonard JN, Buzard DJ, Lehmann J (2009) GPR119 agonists for the treatment of type 2 diabetes. Expert Opin Ther Pat 19:1339–1359

    Article  CAS  PubMed  Google Scholar 

  • Katz LB, Gambale JJ, Rothenberg PL, Vanapalli SR, Vaccaro N, Xi L, Polidori DC, Vets E, Sarich TC, Stein PP (2011) Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential anti diabetes agent, in healthy male subjects. Clin Pharmacol Ther 90:685–692

    Article  CAS  PubMed  Google Scholar 

  • Katz LB, Gambale JJ, Rothenberg PL, Vanapalli SR, Vaccaro N, Xi L, Sarich TC, Stein PP (2012) Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes. Diabetes Obes Metab 14:709–716

    Article  CAS  PubMed  Google Scholar 

  • Koro CE, Bowlin SJ, Bourgeois N, Fedder DO (2004) Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes. Diabetes Care 27:17–20

    Article  PubMed  Google Scholar 

  • Lauffer L, Iakoubov R, Brubaker PL (2008) GPR119: ‘‘double-dipping’’ for better glycemic control. Endocrinology 149:2035–2037

    Article  CAS  PubMed  Google Scholar 

  • Lauffer LM, Iakoubov R, Brubaker PL (2009) GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes 58:1058–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morales J (2011) The pharmacologic basis for clinical differences among GLP-1 receptor agonists and DPP-4 inhibitors. Postgrad Med 123:189–201

    Article  PubMed  Google Scholar 

  • Nilsson C, Raun K, Yan FF, Larsen MO, Tang-Christensen M (2012) Laboratory animals as surrogate models of human obesity. Acta Pharmacol Sin 33:173–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nunez DJ, Bush MA, Collins DA, McMullen SL, Gillmor D, Poss G, Schott R, Feldman PL (2012) Novel and profound lipid effects of GSK1292263, a potent and selective GPR119 agonist, in dyslipidemic subjects. Circulation 126:A9918

    Google Scholar 

  • Nunez DJ, Bush MA, Collins DA, McMullen SL, Gillmor D, Apseloff G, Atiee G, Corsino L, Morrow L, Feldman PL (2014) Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies. PLoS ONE 9:e92494

    Article  PubMed  PubMed Central  Google Scholar 

  • Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, Reynet C (2006) Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab 3:167–175

    Article  CAS  PubMed  Google Scholar 

  • Overton HA, Fyfe MC, Reynet C (2008) GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br J Pharmacol 153(Suppl 1):S76–S81

    CAS  PubMed  Google Scholar 

  • Ritter K, Buning C, Halland N, Pöverlein C, Schwink L (2016) G protein-coupled receptor 119 (GPR119) agonists for the treatment of diabetes: recent progress and prevailing challenges. J Med Chem 59:3579–3592

    Article  CAS  PubMed  Google Scholar 

  • Sakamoto Y, Inoue H, Kawakami S, Miyawaki K, Miyamoto T, Mizuta K, Itakura M (2006) Expression and distribution of Gpr119 in the pancreatic islets of mice and rats: predominant localization in pancreatic polypeptide-secreting PPcells. Biochem Biophys Res Commun 351:474–480

    Article  CAS  PubMed  Google Scholar 

  • Taylor SI, Accili D, Imai Y (1994) Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM? Diabetes 43:735–740

    Article  CAS  PubMed  Google Scholar 

  • UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood–glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865

    Article  Google Scholar 

  • Wacker DA, Wang Y, Broekema M, Rossi K, O’Connor S, Hong Z, Wu G, Malmstrom SE, Hung CP, LaMarre L, Chimalakonda A, Zhang L, Xin L, Cai H, Chu C, Boehm S, Zalaznick J, Ponticiello R, Sereda L, Han SP, Zebo R, Zinker B, Luk CE, Wong R, Everlof G, Li YX, Wu CK, Lee M, Griffen S, Miller KJ, Krupinski J, Robl JA (2014) Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-ethylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119. J Med Chem 57:7499–7508

    Article  CAS  PubMed  Google Scholar 

  • Wang CY, Liao JK (2012) A mouse model of diet-induced obesity and insulin resistance. Methods Mol Biol 821:421–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang JW, Kim HS, Im JH, Kim JW, Jun DW, Lim SC, Lee K, Choi JM, Kim SK, Kang KW (2016) GPR119: a promising target for nonalcoholic fatty liver disease. FASEB J 30:324–335

    Article  CAS  PubMed  Google Scholar 

  • Yip RG, Wolfe MM (2000) GIP biology and fat metabolism. Life Sci 66:91–103

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a Grant of Korean Health Technology R&D project, Ministry of Health & Welfare, Republic of Korea (HI14C1007).

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Authors and Affiliations

  1. Yuhan R&D Institute, 25 Tapsil-ro, Giheung-gu, Yongin, Gyeonggi-do, 17084, Korea

    Yoo Hoi Park, Hyun Ho Choi, Dong Hoon Lee, Soo Yong Chung, Na Yeon Yang, Do Hoon Kim, Mi Kyeong Ju, Tae Dong Han & Su Youn Nam

  2. SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea

    Yoo Hoi Park & Kyu-Won Kim

  3. Crop Biotechnology Institute, GreenBio Science and Technology, Seoul National University, Pyeongchang, 25354, Korea

    Kyu-Won Kim

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  1. Yoo Hoi Park
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Correspondence to Kyu-Won Kim.

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Yoo Hoi Park, Hyun Ho Choi, Dong Hoon Lee, Soo Yong Chung, Na Yeon Yang, Do Hoon Kim, Mi Kyeong Ju, Tae Dong Han and Su Youn Nam are employees of Yuhan Corporation.

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Park, Y.H., Choi, H.H., Lee, D.H. et al. YH18421, a novel GPR119 agonist exerts sustained glucose lowering and weight loss in diabetic mouse model. Arch. Pharm. Res. 40, 772–782 (2017). https://doi.org/10.1007/s12272-017-0925-y

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  • DOI: https://doi.org/10.1007/s12272-017-0925-y

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