Entering the Sugar Rush Era: Revisiting the Antihyperglycemic
Activities of Biguanides after a Century of Metformin Discovery

Xisto   Antonio   de Oliveira Neto; Leticia      Barssotti; Ana   Thereza   Fiori-Duarte; Helena   Cristina   de Lima Barbosa; Daniel   Fábio   Kawano
doi:10.2174/0929867329666220820151959
Abstract

The development of clinically viable metformin analogs is a challenge largely to be overcome. Despite being an extremely efficient drug for the treatment of type 2 diabetes mellitus, multiple studies were conducted seeking to improve its hypoglycemic activity or to ameliorate aspects such as low oral absorption and the incidence of gastrointestinal side effects. Furthermore, efforts have been made to attribute new activities, or even to expand the pre-existing ones, that could enhance its effects on diabetes, such as pancreas-protective, antioxidant, and anti-inflammatory activities. In this paper, we describe the analogs of metformin developed in the last three decades, highlighting the lack of computationally based rational approaches to guide their development. We also discuss this is probably a consequence of how unclear the mechanism of action of the parent drug is and highlight the recent advances towards the establishment of the main molecular target(s) for metformin. We also explored the binding of metformin, buformin and phenformin to the mitochondrial respiratory chain complex I through molecular docking analyses and reviewed the prospects of applying computational tools to improve the success in the development of such analogs. Therefore, it becomes evident that the wide range of molecular targets and the multiple activities displayed by metformin make this drug a promising prototype for developing novel entities, particularly for treating type 2 diabetes mellitus.
Keywords: biguanides, metformin, diabetes, molecular targets, complex I, lactic acidosis
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[1]
Werner, E.A.; Bell, J. The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyandiamide, and methylammonium and dimethylammonium chlorides respectively. J. Chem. Soc. Trans.,  1922, 121(0), 1790-1794.
 [http://dx.doi.org/10.1039/CT9222101790]

[2]
Prugnard, E.; Noel, M. Chemistry and structure-activity relationships of biguanides. In:  Oral Antidiabetics; Kuhlmann, J.; Puls, W., Eds.; Springer: Berlin Heidelberg: Berlin, 1996; pp. 263-285.
 [http://dx.doi.org/10.1007/978-3-662-09127-2_10]

[3]
Sneader, W. Drug discovery: A history, 1st ed; John Wiley & Sons Ltd: Chichester, UK, 2005, pp. 269-286.
 [http://dx.doi.org/10.1002/0470015535]

[4]
Bailey, C.J. Metformin: Historical overview. Diabetologia,  2017, 60(9), 1566-1576.
 [http://dx.doi.org/10.1007/s00125-017-4318-z] [PMID: 28776081]

[5]
U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Aproval package for Glucophage tablets, application number 020357, S010. 1998. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/ nda/98/020357s010_appltr_medr_chemr_EA.pdf (Accessed on: Feb 17, 2022).

[6]
Davies, M.J.; D’Alessio, D.A.; Fradkin, J.; Kernan, W.N.; Mathieu, C.; Mingrone, G.; Rossing, P.; Tsapas, A.; Wexler, D.J.; Buse, J.B. Management of hyperglycemia in type 2 diabetes. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care,  2018, 41(12), 2669-2701.
 [http://dx.doi.org/10.2337/dci18-0033] [PMID: 30291106]

[7]
Belcher, G.; Lambert, C.; Edwards, G.; Urquhart, R.; Matthews, D.R. Safety and tolerability of pioglitazone, metformin, and gliclazide in the treatment of type 2 diabetes. Diabetes Res. Clin. Pract.,  2005, 70(1), 53-62.
 [http://dx.doi.org/10.1016/j.diabres.2005.02.011] [PMID: 16002175]

[8]
Ben Sahra, I.; Le Marchand-Brustel, Y.; Tanti, J-F.; Bost, F. Metformin in cancer therapy: A new perspective for an old antidiabetic drug? Mol. Cancer Ther.,  2010, 9(5), 1092-1099.
 [http://dx.doi.org/10.1158/1535-7163.MCT-09-1186] [PMID: 20442309]

[9]
Bharatam, P.V.; Patel, D.S.; Iqbal, P. Pharmacophoric features of biguanide derivatives: An electronic and structural analysis. J. Med. Chem.,  2005, 48(24), 7615-7622.
 [http://dx.doi.org/10.1021/jm050602z] [PMID: 16302801]

[10]
Marathe, P.H.; Wen, Y.; Norton, J.; Greene, D.S.; Barbhaiya, R.H.; Wilding, I.R. Effect of altered gastric emptying and gastrointestinal motility on metformin absorption. Br. J. Clin. Pharmacol.,  2000, 50(4), 325-332.
 [http://dx.doi.org/10.1046/j.1365-2125.2000.00264.x] [PMID: 11012555]

[11]
Zhou, M.; Xia, L.; Wang, J. Metformin transport by a newly cloned protonstimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab. Dispos.,  2007, 35(10), 1956-1962.
 [http://dx.doi.org/10.1124/dmd.107.015495] [PMID: 17600084]

[12]
He, L.; Wondisford, F.E. Metformin action: Concentrations matter. Cell Metab.,  2015, 21(2), 159-162.
 [http://dx.doi.org/10.1016/j.cmet.2015.01.003] [PMID: 25651170]

[13]
Wang, D.S.; Jonker, J.W.; Kato, Y.; Kusuhara, H.; Schinkel, A.H.; Sugiyama, Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Exp. Ther.,  2002, 302(2), 510-515.
 [http://dx.doi.org/10.1124/jpet.102.034140] [PMID: 12130709]

[14]
Dujic, T.; Zhou, K.; Donnelly, L.A.; Tavendale, R.; Palmer, C.N.A.; Pearson, E.R. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: A GoDARTS study. Diabetes,  2015, 64(5), 1786-1793.
 [http://dx.doi.org/10.2337/db14-1388] [PMID: 25510240]

[15]
Wilcock, C.; Bailey, C.J. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica,  1994, 24(1), 49-57.
 [http://dx.doi.org/10.3109/00498259409043220] [PMID: 8165821]

[16]
McCreight, L.J.; Bailey, C.J.; Pearson, E.R. Metformin and the gastrointestinal tract. Diabetologia,  2016, 59(3), 426-435.
 [http://dx.doi.org/10.1007/s00125-015-3844-9] [PMID: 26780750]

[17]
Hundal, R.S.; Krssak, M.; Dufour, S.; Laurent, D.; Lebon, V.; Chandramouli, V.; Inzucchi, S.E.; Schumann, W.C.; Petersen, K.F.; Landau, B.R.; Shulman, G.I. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes,  2000, 49(12), 2063-2069.
 [http://dx.doi.org/10.2337/diabetes.49.12.2063] [PMID: 11118008]

[18]
Hollunger, G. Guanidines and oxidative phosphorylations. Acta Pharmacol. Toxicol. (Copenh.),  1955, 11(Suppl. 1), 1-84.
 [http://dx.doi.org/10.1111/j.1600-0773.1955.tb02972.x] [PMID: 13248572]

[19]
Schäfer, G. Site-specific uncoupling and inhibition of oxidative phosphorylation by biguanides. II. Biochim. Biophys. Acta,  1969, 172(2), 334-337.
 [http://dx.doi.org/10.1016/0005-2728(69)90077-2] [PMID: 4304727]

[20]
Owen, M.R.; Doran, E.; Halestrap, A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J.,  2000, 348(Pt 3), 607-614.
 [http://dx.doi.org/10.1042/bj3480607] [PMID: 10839993]

[21]
El-Mir, M.Y.; Nogueira, V.; Fontaine, E.; Avéret, N.; Rigoulet, M.; Leverve, X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem.,  2000, 275(1), 223-228.
 [http://dx.doi.org/10.1074/jbc.275.1.223] [PMID: 10617608]

[22]
Bridges, H.R.; Jones, A.J.Y.; Pollak, M.N.; Hirst, J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem. J.,  2014, 462(3), 475-487.
 [http://dx.doi.org/10.1042/BJ20140620] [PMID: 25017630]

[23]
Wang, Y.; An, H.; Liu, T.; Qin, C.; Sesaki, H.; Guo, S.; Radovick, S.; Hussain, M.; Maheshwari, A.; Wondisford, F.E.; O’Rourke, B.; He, L. Metformin improves mitochondrial respiratory activity through activation of AMPK. Cell Rep.,  2019, 29(6), 1511-1523.e5.
 [http://dx.doi.org/10.1016/j.celrep.2019.09.070] [PMID: 31693892]

[24]
Vial, G.; Detaille, D.; Guigas, B. Role of mitochondria in the mechanism(s) of action of metformin. Front. Endocrinol. (Lausanne),  2019, 10, 294.
 [http://dx.doi.org/10.3389/fendo.2019.00294] [PMID: 31133988]

[25]
LaMoia, T.E.; Shulman, G.I. Cellular and molecular mechanisms of metformin action. Endocr. Rev.,  2021, 42(1), 77-96.
 [http://dx.doi.org/10.1210/endrev/bnaa023] [PMID: 32897388]

[26]
Fontaine, E. Metformin-induced mitochondrial complex I inhibition: Facts, uncertainties, and consequences. Front. Endocrinol. (Lausanne),  2018, 9, 753.
 [http://dx.doi.org/10.3389/fendo.2018.00753] [PMID: 30619086]

[27]
Pernicova, I.; Korbonits, M. Metformin-mode of action and clinical implications for diabetes and cancer. Nat. Rev. Endocrinol.,  2014, 10(3), 143-156.
 [http://dx.doi.org/10.1038/nrendo.2013.256] [PMID: 24393785]

[28]
Feng, J.; Wang, X.; Ye, X.; Ares, I.; Lopez-Torres, B.; Martínez, M.; Martínez-Larrañaga, M-R.; Wang, X.; Anadón, A.; Martínez, M-A. Mitochondria as an important target of metformin: The mechanism of action, toxic and side effects, and new therapeutic applications. Pharmacol. Res.,  2022, 177, 106114.
 [http://dx.doi.org/10.1016/j.phrs.2022.106114] [PMID: 35124206]

[29]
Gormsen, L.C.; Sundelin, E.I.; Jensen, J.B.; Vendelbo, M.H.; Jakobsen, S.; Munk, O.L.; Hougaard Christensen, M.M.; Brøsen, K.; Frøkiær, J.; Jessen, N. In vivo imaging of human 11C-metformin in peripheral organs: Dosimetry, biodistribution, and kinetic analyses. J. Nucl. Med.,  2016, 57(12), 1920-1926.
 [http://dx.doi.org/10.2967/jnumed.116.177774] [PMID: 27469359]

[30]
He, L. Metformin and systemic metabolism. Trends Pharmacol. Sci.,  2020, 41(11), 868-881.
 [http://dx.doi.org/10.1016/j.tips.2020.09.001] [PMID: 32994049]

[31]
Boukalova, S.; Stursa, J.; Werner, L.; Ezrova, Z.; Cerny, J.; Bezawork-Geleta, A.; Pecinova, A.; Dong, L.; Drahota, Z.; Neuzil, J. Mitochondrial targeting of metformin enhances its activity against pancreatic cancer. Mol. Cancer Ther.,  2016, 15(12), 2875-2886.
 [http://dx.doi.org/10.1158/1535-7163.MCT-15-1021] [PMID: 27765848]

[32]
Giachin, G.; Bouverot, R.; Acajjaoui, S.; Pantalone, S.; Soler-López, M. Dynamics of human mitochondrial complex I assembly: Implications for neurodegenerative diseases. Front. Mol. Biosci.,  2016, 3, 43.
 [http://dx.doi.org/10.3389/fmolb.2016.00043] [PMID: 27597947]

[33]
Rahman, S.; Ahsan, T.; Hossain, R.; Ahmed, T.; Sajib, A.A. molecular mechanism of metformin associated lactic acidosis (MALA)-an in silico exploration. Curr. Pharmacogenom. Person. Med.,  2018, 16(3), 199-209.
 [http://dx.doi.org/10.2174/1875692117666181207121639]

[34]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera-a visualization system for exploratory research and analysis. J. Comput. Chem.,  2004, 25(13), 1605-1612.
 [http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]

[35]
Guo, R.; Zong, S.; Wu, M.; Gu, J.; Yang, M. Architecture of human mitochondrial respiratory megacomplex I2III2IV2. Cell,  2017, 170(6), 1247-1257.e12.
 [http://dx.doi.org/10.1016/j.cell.2017.07.050] [PMID: 28844695]

[36]
Blow, D.M. Outline of crystallography for biologists; Oxford University Press: Oxford, UK, 2002. 
 [http://dx.doi.org/10.1093/oso/9780198510512.001.0001]

[37]
Oliveira, S.H.P.; Ferraz, F.A.N.; Honorato, R.V.; Xavier-Neto, J.; Sobreira, T.J.P.; de Oliveira, P.S.L. KVFinder: Steered identification of protein cavities as a PyMOL plugin. BMC Bioinformatics,  2014, 15(1), 197.
 [http://dx.doi.org/10.1186/1471-2105-15-197] [PMID: 24938294]

[38]
Oliveira Neto, X.A.; Alves, A.C.S.; Dias, R.A., Junior; Rodrigues, R.P.; Lancellotti, M.; Almeida, W.P.; Kawano, D.F. Molecular docking reveals the binding modes of anticancer alkylphospholipids and lysophosphatidylcholine within the catalytic domain of cytidine triphosphate: Phosphocholine cytidyltransferase. Eur. J. Lipid Sci. Technol.,  2020, 122(7), 1900422.
 [http://dx.doi.org/10.1002/ejlt.201900422]

[39]
Stierand, K.; Rarey, M. PoseView-Molecular interaction patterns at a glance. J. Cheminform.,  2010, 2(S1), 50.
 [http://dx.doi.org/10.1186/1758-2946-2-S1-P50]

[40]
Gehlhaar, D.K.; Verkhivker, G.M.; Rejto, P.A.; Sherman, C.J.; Fogel, D.B.; Fogel, L.J.; Freer, S.T. Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: Conformationally flexible docking by evolutionary programming. Chem. Biol.,  1995, 2(5), 317-324.
 [http://dx.doi.org/10.1016/1074-5521(95)90050-0] [PMID: 9383433]

[41]
Dykens, J.A.; Jamieson, J.; Marroquin, L.; Nadanaciva, S.; Billis, P.A.; Will, Y. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol. Appl. Pharmacol.,  2008, 233(2), 203-210.
 [http://dx.doi.org/10.1016/j.taap.2008.08.013] [PMID: 18817800]

[42]
Piel, S.; Ehinger, J.K.; Elmér, E.; Hansson, M.J. Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition. Acta Physiol. (Oxf.),  2015, 213(1), 171-180.
 [http://dx.doi.org/10.1111/apha.12311] [PMID: 24801139]

[43]
Plumb, B.; Parker, A.; Wong, P. Feeling blue with metformin-associated lactic acidosis. BMJ Case Rep.,  2013, 2013(1), 2-5.
 [http://dx.doi.org/10.1136/bcr-2013-008855] [PMID: 23456165]

[44]
Hinke, S.A.; Martens, G.A.; Cai, Y.; Finsi, J.; Heimberg, H.; Pipeleers, D.; Van de Casteele, M. Methyl succinate antagonises biguanide-induced AMPK-activation and death of pancreatic β-cells through restoration of mitochondrial electron transfer. Br. J. Pharmacol.,  2007, 150(8), 1031-1043.
 [http://dx.doi.org/10.1038/sj.bjp.0707189] [PMID: 17339833]

[45]
Piel, S.; Ehinger, J.K.; Chamkha, I.; Frostner, E.Å.; Sjövall, F.; Elmér, E.; Hansson, M.J. Bioenergetic bypass using cell-permeable succinate, but not methylene blue, attenuates metformin-induced lactate production. Intensive Care Med. Exp.,  2018, 6(1), 22.
 [http://dx.doi.org/10.1186/s40635-018-0186-1] [PMID: 30069806]

[46]
Protti, A. Succinate and the shortcut to the cure of metformin-induced lactic acidosis. Intensive Care Med. Exp.,  2018, 6(1), 35.
 [http://dx.doi.org/10.1186/s40635-018-0202-5] [PMID: 30251134]

[47]
Madiraju, A.K.; Erion, D.M.; Rahimi, Y.; Zhang, X.M.; Braddock, D.T.; Albright, R.A.; Prigaro, B.J.; Wood, J.L.; Bhanot, S.; MacDonald, M.J.; Jurczak, M.J.; Camporez, J.P.; Lee, H-Y.; Cline, G.W.; Samuel, V.T.; Kibbey, R.G.; Shulman, G.I. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature,  2014, 510(7506), 542-546.
 [http://dx.doi.org/10.1038/nature13270] [PMID: 24847880]

[48]
Ouyang, J.; Parakhia, R.A.; Ochs, R.S. Metformin activates AMP kinase through inhibition of AMP deaminase. J. Biol. Chem.,  2011, 286(1), 1-11.
 [http://dx.doi.org/10.1074/jbc.M110.121806] [PMID: 21059655]

[49]
Polianskyte-Prause, Z.; Tolvanen, T.A.; Lindfors, S.; Dumont, V.; Van, M.; Wang, H.; Dash, S.N.; Berg, M.; Naams, J.B.; Hautala, L.C.; Nisen, H.; Mirtti, T.; Groop, P.H.; Wähälä, K.; Tienari, J.; Lehtonen, S. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity. FASEB J.,  2019, 33(2), 2858-2869.
 [http://dx.doi.org/10.1096/fj.201800529RR] [PMID: 30321069]

[50]
Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M.F.; Goodyear, L.J.; Moller, D.E. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest.,  2001, 108(8), 1167-1174.
 [http://dx.doi.org/10.1172/JCI13505] [PMID: 11602624]

[51]
Foretz, M.; Hébrard, S.; Leclerc, J.; Zarrinpashneh, E.; Soty, M.; Mithieux, G.; Sakamoto, K.; Andreelli, F.; Viollet, B. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest.,  2010, 120(7), 2355-2369.
 [http://dx.doi.org/10.1172/JCI40671] [PMID: 20577053]

[52]
Lee, J.O.; Lee, S.K.; Jung, J.H.; Kim, J.H.; You, G.Y.; Kim, S.J.; Park, S.H.; Uhm, K-O.; Kim, H.S. Metformin induces Rab4 through AMPK and modulates GLUT4 translocation in skeletal muscle cells. J. Cell. Physiol.,  2011, 226(4), 974-981.
 [http://dx.doi.org/10.1002/jcp.22410] [PMID: 20857458]

[53]
Koo, S.H.; Flechner, L.; Qi, L.; Zhang, X.; Screaton, R.A.; Jeffries, S.; Hedrick, S.; Xu, W.; Boussouar, F.; Brindle, P.; Takemori, H.; Montminy, M. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature,  2005, 437(7062), 1109-1111.
 [http://dx.doi.org/10.1038/nature03967] [PMID: 16148943]

[54]
Screaton, R.A.; Conkright, M.D.; Katoh, Y.; Best, J.L.; Canettieri, G.; Jeffries, S.; Guzman, E.; Niessen, S.; Yates, J.R., III; Takemori, H.; Okamoto, M.; Montminy, M. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell,  2004, 119(1), 61-74.
 [http://dx.doi.org/10.1016/j.cell.2004.09.015] [PMID: 15454081]

[55]
Miller, R.A.; Chu, Q.; Xie, J.; Foretz, M.; Viollet, B.; Birnbaum, M.J. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature,  2013, 494(7436), 256-260.
 [http://dx.doi.org/10.1038/nature11808] [PMID: 23292513]

[56]
Konopka, A.R.; Esponda, R.R.; Robinson, M.M.; Johnson, M.L.; Carter, R.E.; Schiavon, M.; Cobelli, C.; Wondisford, F.E.; Lanza, I.R.; Nair, K.S. Hyperglucagonemia mitigates the effect of metformin on glucose production in prediabetes. Cell Rep.,  2016, 15(7), 1394-1400.
 [http://dx.doi.org/10.1016/j.celrep.2016.04.024] [PMID: 27160898]

[57]
Bijarnia-Mahay, S.; Bhatia, S.; Arora, V. Fructose-1,6-bisphosphatase deficiency. In: GeneReviews®; Adam, M.P., Ed.; Seattle: University of Washington: Washington, 2019. 

[58]
Hunter, R.W.; Hughey, C.C.; Lantier, L.; Sundelin, E.I.; Peggie, M.; Zeqiraj, E.; Sicheri, F.; Jessen, N.; Wasserman, D.H.; Sakamoto, K. Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat. Med.,  2018, 24(9), 1395-1406.
 [http://dx.doi.org/10.1038/s41591-018-0159-7] [PMID: 30150719]

[59]
Madiraju, A.K.; Qiu, Y.; Perry, R.J.; Rahimi, Y.; Zhang, X-M.; Zhang, D.; Camporez, J.G.; Cline, G.W.; Butrico, G.M.; Kemp, B.E.; Casals, G.; Steinberg, G.R.; Vatner, D.F.; Petersen, K.F.; Shulman, G.I. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat. Med.,  2018, 24(9), 1384-1394.
 [http://dx.doi.org/10.1038/s41591-018-0125-4] [PMID: 30038219]

[60]
Alshawi, A.; Agius, L. Low metformin causes a more oxidized mitochondrial NADH/NAD redox state in hepatocytes and inhibits gluconeogenesis by a redox-independent mechanism. J. Biol. Chem.,  2019, 294(8), 2839-2853.
 [http://dx.doi.org/10.1074/jbc.RA118.006670] [PMID: 30591586]

[61]
Reitz, A.B.; Tuman, R.W.; Marchione, C.S.; Jordan, A.D., Jr; Bowden, C.R.; Maryanoff, B.E. Carbohydrate biguanides as potential hypoglycemic agents. J. Med. Chem.,  1989, 32(9), 2110-2116.
 [http://dx.doi.org/10.1021/jm00129a015] [PMID: 2769683]

[62]
Liu, Z.; Li, J.; Zeng, Z.; Liu, M.; Wang, M. The antidiabetic effects of cysteinyl metformin, a newly synthesized agent, in alloxan- and streptozocin-induced diabetic rats. Chem. Biol. Interact.,  2008, 173(1), 68-75.
 [http://dx.doi.org/10.1016/j.cbi.2007.11.012] [PMID: 18377884]

[63]
Huttunen, K.M.; Mannila, A.; Laine, K.; Kemppainen, E.; Leppänen, J.; Vepsäläinen, J.; Järvinen, T.; Rautio, J. The first bioreversible prodrug of metformin with improved lipophilicity and enhanced intestinal absorption. J. Med. Chem.,  2009, 52(14), 4142-4148.
 [http://dx.doi.org/10.1021/jm900274q] [PMID: 19522462]

[64]
Huttunen, K.M.; Leppänen, J.; Vepsäläinen, J.; Sirviö, J.; Laine, K.; Rautio, J. In vitro and in vivo evaluation of a sulfenamide prodrug of basic metformin. J. Pharm. Sci.,  2012, 101(8), 2854-2860.
 [http://dx.doi.org/10.1002/jps.23221] [PMID: 22648910]

[65]
Rautio, J.; Vernerová, M.; Aufderhaar, I.; Huttunen, K.M. Glutathione-S-transferase selective release of metformin from its sulfonamide prodrug. Bioorg. Med. Chem. Lett.,  2014, 24(21), 5034-5036.
 [http://dx.doi.org/10.1016/j.bmcl.2014.09.019] [PMID: 25248681]

[66]
Markowicz-Piasecka, M.; Sikora, J.; Zajda, A.; Huttunen, K.M. Novel halogenated sulfonamide biguanides with anti-coagulation properties. Bioorg. Chem.,  2020, 94, 103444.
 [http://dx.doi.org/10.1016/j.bioorg.2019.103444] [PMID: 31776031]

[67]
Crabtree, T.S.; DeFronzo, R.A.; Ryder, R.E.J.; Bailey, C.J. Imeglimin, a novel, first in-class, blood glucose-lowering agent: A systematic review and meta-analysis of clinical evidence. Br. J. Diabetes,  2020, 20(1), 28-31.
 [http://dx.doi.org/10.15277/bjd.2020.247]

[68]
Yaribeygi, H.; Maleki, M.; Sathyapalan, T.; Jamialahmadi, T.; Sahebkar, A. Molecular mechanisms by which imeglimin improves glucose homeostasis. J. Diabetes Res.,  2020, 2020, 8768954.
 [http://dx.doi.org/10.1155/2020/8768954] [PMID: 32215274]

[69]
Yendapally, R.; Sikazwe, D.; Kim, S.S.; Ramsinghani, S.; Fraser-Spears, R.; Witte, A.P.; La-Viola, B. A review of phenformin, metformin, and imeglimin. Drug Dev. Res.,  2020, 81(4), 390-401.
 [http://dx.doi.org/10.1002/ddr.21636] [PMID: 31916629]

[70]
Johansson, K.S.; Brønden, A.; Knop, F.K.; Christensen, M.B. Clinical pharmacology of imeglimin for the treatment of type 2 diabetes. Expert Opin. Pharmacother.,  2020, 21(8), 871-882.
 [http://dx.doi.org/10.1080/14656566.2020.1729123] [PMID: 32108532]

[71]
Poxel, S.A. TWYMEEG® (Imeglimin) 2022. Available from: https://www.poxelpharma.com/en_us/pipeline/diabetes (Accessed on: Apr 28, 2022).

[72]
Cravo, D.; Helmreich, M. Separation of triazine derivatives enantiomers using tartaric acid. Patent US8742103B2, 2012.

[73]
Fouqueray, P.; Leverve, X.; Fontaine, E.; Baquié, M.; Wollheim, C. Imeglimin-a new oral anti-diabetic that targets the three key defects of type 2 diabetes. J. Diabetes Metab.,  2011, 2(4), 1000126.
 [http://dx.doi.org/10.4172/2155-6156.1000126]

[74]
Vial, G.; Chauvin, M.A.; Bendridi, N.; Durand, A.; Meugnier, E.; Madec, A.M.; Bernoud-Hubac, N.; Pais de Barros, J.P.; Fontaine, É.; Acquaviva, C.; Hallakou-Bozec, S.; Bolze, S.; Vidal, H.; Rieusset, J. Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model. Diabetes,  2015, 64(6), 2254-2264.
 [http://dx.doi.org/10.2337/db14-1220] [PMID: 25552598]

[75]
Perry, R.J.; Cardone, R.L.; Petersen, M.C.; Zhang, D.; Fouqueray, P.; Hallakou-Bozec, S.; Bolze, S.; Shulman, G.I.; Petersen, K.F.; Kibbey, R.G. Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents. Am. J. Physiol. Endocrinol. Metab.,  2016, 311(2), E461-E470.
 [http://dx.doi.org/10.1152/ajpendo.00009.2016] [PMID: 27406738]

[76]
Detaille, D.; Vial, G.; Borel, A.L.; Cottet-Rouselle, C.; Hallakou-Bozec, S.; Bolze, S.; Fouqueray, P.; Fontaine, E. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration. Cell Death Discov.,  2016, 2(1), 15072.
 [http://dx.doi.org/10.1038/cddiscovery.2015.72] [PMID: 27551496]

[77]
Pirags, V.; Lebovitz, H.; Fouqueray, P. Imeglimin, a novel glimin oral antidiabetic, exhibits a good efficacy and safety profile in type 2 diabetic patients. Diabetes Obes. Metab.,  2012, 14(9), 852-858.
 [http://dx.doi.org/10.1111/j.1463-1326.2012.01611.x] [PMID: 22519919]

[78]
Pacini, G.; Mari, A.; Fouqueray, P.; Bolze, S.; Roden, M. Imeglimin increases glucose-dependent insulin secretion and improves β-cell function in patients with type 2 diabetes. Diabetes Obes. Metab.,  2015, 17(6), 541-545.
 [http://dx.doi.org/10.1111/dom.12452] [PMID: 25694060]

[79]
Fouqueray, P.; Pirags, V.; Inzucchi, S.E.; Bailey, C.J.; Schernthaner, G.; Diamant, M.; Lebovitz, H.E. The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care,  2013, 36(3), 565-568.
 [http://dx.doi.org/10.2337/dc12-0453] [PMID: 23160726]

[80]
Fouqueray, P.; Pirags, V.; Diamant, M.; Schernthaner, G.; Lebovitz, H.E.; Inzucchi, S.E.; Bailey, C.J. The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy. Diabetes Care,  2014, 37(7), 1924-1930.
 [http://dx.doi.org/10.2337/dc13-2349] [PMID: 24722500]

[81]
Abbas, S.Y.; Basyouni, W.M.; El-Bayouki, K.A.M.; Abdel-Rahman, R.F. Synthesis and Evaluation of 1-substituted-biguanide derivatives as anti-diabetic agents for type II diabetes insulin resistant. Drug Res. (Stuttg.),  2016, 66(7), 377-383.
 [http://dx.doi.org/10.1055/s-0042-107349] [PMID: 27191826]

[82]
Abbas, S.Y.; Basyouni, W.M.; El-Bayouk, K.A.M.; Tohamy, W.M.; Aly, H.F.; Arafa, A.; Soliman, M.S. New biguanides as anti-diabetic agents part I: Synthesis and evaluation of 1-substituted biguanide derivatives as anti-diabetic agents of type II diabetes insulin resistant. Drug Res. (Stuttg.),  2017, 67(10), 557-563.
 [http://dx.doi.org/10.1055/s-0043-102692] [PMID: 28651259]

[83]
Basyouni, W.M.; Abbas, S.Y.; El Shehry, M.F.; El-Bayouki, K.A.M.; Aly, H.F.; Arafa, A.; Soliman, M.S. New biguanides as anti-diabetic agents, part II: Synthesis and anti-diabetic properties evaluation of 1-arylamidebiguanide derivatives as agents of insulin resistant type II diabetes. Arch. Pharm. (Weinheim),  2017, 350(11), 1700183.
 [http://dx.doi.org/10.1002/ardp.201700183] [PMID: 29027251]

[84]
Mahdi, M.F.; Arif, I.S.; Jubair, N.K. Design, synthesis and preliminary pharmacological evaluation of new metformin derivatives. Int. J. Pharm. Pharm. Sci.,  2016, 9(1), 239-245.
 [http://dx.doi.org/10.22159/ijpps.2017v9i1.15250]

[85]
Ramya, V.; Vembu, S.; Ariharasivakumar, G.; Gopalakrishnan, M. Synthesis, characterisation, molecular docking, anti-microbial and anti-diabetic screening of substituted 4-indolylphenyl-6-arylpyrimidine-2-imine Derivatives. Drug Res. (Stuttg.),  2017, 67(9), 515-526.
 [http://dx.doi.org/10.1055/s-0043-106444] [PMID: 28628926]

[86]
Cao, H.; Liao, S.; Zhong, W.; Xiao, X.; Zhu, J.; Li, W.; Wu, X.; Feng, Y. Synthesis, characterization, and biological evaluations of 1,3,5-triazine derivatives of metformin cyclization with berberine and magnolol in the presence of sodium methylate. Molecules,  2017, 22(10), 1752.
 [http://dx.doi.org/10.3390/molecules22101752] [PMID: 29057810]

[87]
Jia, D.; Li, Z.; Gao, Y.; Feng, Y.; Li, W. A novel triazine ring compound (MD568) exerts in vivo and in vitro effects on lipid metabolism. Biomed. Pharmacother.,  2018, 103, 790-799.
 [http://dx.doi.org/10.1016/j.biopha.2018.04.065] [PMID: 29684858]

[88]
Chen, D.; Jia, D.; Wu, X.; Shi, K.; Ren, C.; Dou, Y.; Guo, M.; Wang, J.; Ma, M.; Wu, Z.; Shi, H-Y.; Li, W.; Feng, Y.; Wu, F. A novel metformin derivative showed improvement of lipid metabolism in obese rats with type 2 diabetes. Clin. Exp. Pharmacol. Physiol.,  2020, 47(8), 1382-1392.
 [http://dx.doi.org/10.1111/1440-1681.13302] [PMID: 32155673]

[89]
Jia, D.; Li, Z.W.; Zhou, X.; Gao, Y.; Feng, Y.; Ma, M.; Wu, Z.; Li, W. A novel berberine-metformin hybrid compound exerts therapeutic effects on obese type 2 diabetic rats. Clin. Exp. Pharmacol. Physiol.,  2019, 46(6), 533-544.
 [http://dx.doi.org/10.1111/1440-1681.13085] [PMID: 30883863]

[90]
Gutiérrez-Lara, E.; Martínez-Conde, C.; Rosales-Ortega, E.; Ramírez-Espinosa, J.J.; Rivera-Leyva, J.C.; Centurión, D.; Carvajal, K.; Ortega-Cuellar, D.; Estrada-Soto, S.; Navarrete-Vázquez, G. Synthesis and in vitro AMPK activation of cycloalkyl/ alkarylbiguanides with robust in vivo antihyperglycemic action. J. Chem.,  2017, 2017, 1212609.
 [http://dx.doi.org/10.1155/2017/1212609]
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DOI https://dx.doi.org/10.2174/0929867329666220820151959	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
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