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Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes.

Bebernitz GR, Beaulieu V, Dale BA, Deacon R, Duttaroy A, Gao J, Grondine MS, Gupta RC, Kakmak M, Kavana M, Kirman LC, Liang J, Maniara WM, Munshi S, Nadkarni SS, Schuster HF, Stams T, St Denny I, Taslimi PM, Vash B, Caplan SL
J Med Chem 52 6142-52 (2009)
Cited: 55 times
EuropePMC logo PMID: 19746978

Abstract

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alphaK(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

Reviews - 3imx mentioned but not cited (1)

  1. Evaluation of the Anti-Diabetic Activity of Some Common Herbs and Spices: Providing New Insights with Inverse Virtual Screening. Pereira ASP, Banegas-Luna AJ, Peña-García J, Pérez-Sánchez H, Apostolides Z. Molecules 24 E4030 (2019)

Articles - 3imx mentioned but not cited (10)

  1. Strain analysis of protein structures and low dimensionality of mechanical allosteric couplings. Mitchell MR, Tlusty T, Leibler S. Proc Natl Acad Sci U S A 113 E5847-E5855 (2016)
  2. Structural studies of ROK fructokinase YdhR from Bacillus subtilis: insights into substrate binding and fructose specificity. Nocek B, Stein AJ, Jedrzejczak R, Cuff ME, Li H, Volkart L, Joachimiak A. J Mol Biol 406 325-342 (2011)
  3. Exploring African Medicinal Plants for Potential Anti-Diabetic Compounds with the DIA-DB Inverse Virtual Screening Web Server. Pereira ASP, den Haan H, Peña-García J, Moreno MM, Pérez-Sánchez H, Apostolides Z. Molecules 24 E2002 (2019)
  4. A Drug-Target Network-Based Approach to Evaluate the Efficacy of Medicinal Plants for Type II Diabetes Mellitus. Gu J, Chen L, Yuan G, Xu X. Evid Based Complement Alternat Med 2013 203614 (2013)
  5. Design, synthesis and evaluation of novel 3,5-disubstituted benzamide derivatives as allosteric glucokinase activators. Grewal AS, Kharb R, Prasad DN, Dua JS, Lather V. BMC Chem 13 2 (2019)
  6. Computation Screening of Multi-Target Antidiabetic Properties of Phytochemicals in Common Edible Mediterranean Plants. Goulas V, Banegas-Luna AJ, Constantinou A, Pérez-Sánchez H, Barbouti A. Plants (Basel) 11 1637 (2022)
  7. Computational Study of Asian Propolis Compounds as Potential Anti-Type 2 Diabetes Mellitus Agents by Using Inverse Virtual Screening with the DIA-DB Web Server, Tanimoto Similarity Analysis, and Molecular Dynamic Simulation. Syaifie PH, Harisna AH, Nasution MAF, Arda AG, Nugroho DW, Jauhar MM, Mardliyati E, Maulana NN, Rochman NT, Noviyanto A, Banegas-Luna AJ, Pérez-Sánchez H. Molecules 27 3972 (2022)
  8. Design, synthesis, in silico, and in vitro evaluation of benzylbenzimidazolone derivatives as potential drugs on α-glucosidase and glucokinase as pharmacological targets. Santos-Ballardo CL, Montes-Ávila J, Rendon-Maldonado JG, Ramos-Payan R, Montaño S, Sarmiento-Sánchez JI, Acosta-Cota SJ, Ochoa-Terán A, Bastidas-Bastidas PJ, Osuna-Martínez U. RSC Adv 13 21153-21162 (2023)
  9. Fishing the Targets of Bioactive Compounds from Psidium guajava L. Leaves in the Context of Diabetes. Díaz-de-Cerio E, Girón F, Pérez-Garrido A, Pereira ASP, Gabaldón-Hernández JA, Verardo V, Segura Carretero A, Pérez-Sánchez H. Int J Mol Sci 24 5761 (2023)
  10. In silico docking based screening of constituents from Persian shallot as modulators of human glucokinase. Kaur A, Thakur S, Deswal G, Chopra B, Dhingra AK, Guarve K, Grewal AS. J Diabetes Metab Disord 22 547-570 (2023)


Reviews citing this publication (9)

  1. Liver glucokinase: An overview on the regulatory mechanisms of its activity. Massa ML, Gagliardino JJ, Francini F. IUBMB Life 63 1-6 (2011)
  2. Modulation of Glucokinase Regulatory Protein: A Double-Edged Sword? Brouwers MCGJ, Jacobs C, Bast A, Stehouwer CDA, Schaper NC. Trends Mol Med 21 583-594 (2015)
  3. Strategies for the design of hepatoselective glucokinase activators to treat type 2 diabetes. Pfefferkorn JA. Expert Opin Drug Discov 8 319-330 (2013)
  4. Homotropic allosteric regulation in monomeric mammalian glucokinase. Larion M, Miller BG. Arch Biochem Biophys 519 103-111 (2012)
  5. Molecular targeting of the GK-GKRP pathway in diabetes. Hale C, Lloyd DJ, Pellacani A, Véniant MM. Expert Opin Ther Targets 19 129-139 (2015)
  6. Identification of YH-GKA, a novel benzamide glucokinase activator as therapeutic candidate for type 2 diabetes mellitus. Park K. Arch Pharm Res 35 2029-2033 (2012)
  7. Discontinued drugs in 2012: endocrine and metabolic. Colca JR. Expert Opin Investig Drugs 22 1305-1313 (2013)
  8. Insulin Regulation of Hepatic Lipid Homeostasis. Uehara K, Santoleri D, Whitlock AEG, Titchenell PM. Compr Physiol 13 4785-4809 (2023)
  9. New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment. Haddad D, Dsouza VS, Al-Mulla F, Al Madhoun A. Int J Mol Sci 25 571 (2024)

Articles citing this publication (35)

  1. Glucokinase links Krüppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease. Bechmann LP, Gastaldelli A, Vetter D, Patman GL, Pascoe L, Hannivoort RA, Lee UE, Fiel I, Muñoz U, Ciociaro D, Lee YM, Buzzigoli E, Miele L, Hui KY, Bugianesi E, Burt AD, Day CP, Mari A, Agius L, Walker M, Friedman SL, Reeves HL. Hepatology 55 1083-1093 (2012)
  2. Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase. Choi JM, Seo MH, Kyeong HH, Kim E, Kim HS. Proc Natl Acad Sci U S A 110 10171-10176 (2013)
  3. Small molecule glucokinase activators disturb lipid homeostasis and induce fatty liver in rodents: a warning for therapeutic applications in humans. De Ceuninck F, Kargar C, Ilic C, Caliez A, Rolin JO, Umbdenstock T, Vinson C, Combettes M, de Fanti B, Harley E, Sadlo M, Lefèvre AL, Broux O, Wierzbicki M, Fourquez JM, Perron-Sierra F, Kotschy A, Ktorza A. Br J Pharmacol 168 339-353 (2013)
  4. Insights into mechanism of glucokinase activation: observation of multiple distinct protein conformations. Liu S, Ammirati MJ, Song X, Knafels JD, Zhang J, Greasley SE, Pfefferkorn JA, Qiu X. J Biol Chem 287 13598-13610 (2012)
  5. Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase. Larion M, Salinas RK, Bruschweiler-Li L, Miller BG, Brüschweiler R. PLoS Biol 10 e1001452 (2012)
  6. The active conformation of human glucokinase is not altered by allosteric activators. Petit P, Antoine M, Ferry G, Boutin JA, Lagarde A, Gluais L, Vincentelli R, Vuillard L. Acta Crystallogr D Biol Crystallogr 67 929-935 (2011)
  7. A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Szlyk B, Braun CR, Ljubicic S, Patton E, Bird GH, Osundiji MA, Matschinsky FM, Walensky LD, Danial NN. Nat Struct Mol Biol 21 36-42 (2014)
  8. Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat. Futamura M, Yao J, Li X, Bergeron R, Tran JL, Zycband E, Woods J, Zhu Y, Shao Q, Maruki-Uchida H, Goto-Shimazaki H, Langdon RB, Erion MD, Eiki J, Zhou YP. Diabetologia 55 1071-1080 (2012)
  9. Pharmacokinetic and pharmacodynamic properties of the glucokinase activator MK-0941 in rodent models of type 2 diabetes and healthy dogs. Eiki J, Nagata Y, Futamura M, Sasaki-Yamamoto K, Iino T, Nishimura T, Chiba M, Ohyama S, Yoshida-Yoshimioto R, Fujii K, Hosaka H, Goto-Shimazaki H, Kadotani A, Ohe T, Lin S, Langdon RB, Berger JP. Mol Pharmacol 80 1156-1165 (2011)
  10. The hepatoselective glucokinase activator PF-04991532 ameliorates hyperglycemia without causing hepatic steatosis in diabetic rats. Erion DM, Lapworth A, Amor PA, Bai G, Vera NB, Clark RW, Yan Q, Zhu Y, Ross TT, Purkal J, Gorgoglione M, Zhang G, Bonato V, Baker L, Barucci N, D'Aquila T, Robertson A, Aiello RJ, Yan J, Trimmer J, Rolph TP, Pfefferkorn JA. PLoS One 9 e97139 (2014)
  11. Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. Vella A, Freeman JLR, Dunn I, Keller K, Buse JB, Valcarce C. Sci Transl Med 11 eaau3441 (2019)
  12. Discovery of 3-(4-methanesulfonylphenoxy)-N-[1-(2-methoxy-ethoxymethyl)-1H-pyrazol-3-yl]-5-(3-methylpyridin-2-yl)-benzamide as a novel glucokinase activator (GKA) for the treatment of type 2 diabetes mellitus. Park K, Lee BM, Hyun KH, Lee DH, Choi HH, Kim H, Chong W, Kim KB, Nam SY. Bioorg Med Chem 22 2280-2293 (2014)
  13. Discovery of a novel phenylethyl benzamide glucokinase activator for the treatment of type 2 diabetes mellitus. Park K, Lee BM, Kim YH, Han T, Yi W, Lee DH, Choi HH, Chong W, Lee CH. Bioorg Med Chem Lett 23 537-542 (2013)
  14. Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution. Pfefferkorn JA, Litchfield J, Hutchings R, Cheng XM, Larsen SD, Auerbach B, Bush MR, Lee C, Erasga N, Bowles DM, Boyles DC, Lu G, Sekerke C, Askew V, Hanselman JC, Dillon L, Lin Z, Robertson A, Olsen K, Boustany C, Atkinson K, Goosen TC, Sahasrabudhe V, Chupka J, Duignan DB, Feng B, Scialis R, Kimoto E, Bi YA, Lai Y, El-Kattan A, Bakker-Arkema R, Barclay P, Kindt E, Le V, Mandema JW, Milad M, Tait BD, Kennedy R, Trivedi BK, Kowala M. Bioorg Med Chem Lett 21 2725-2731 (2011)
  15. The use of docking-based comparative intermolecular contacts analysis to identify optimal docking conditions within glucokinase and to discover of new GK activators. Taha MO, Habash M, Khanfar MA, Khanfar MA. J Comput Aided Mol Des 28 509-547 (2014)
  16. Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators. Mao W, Ning M, Liu Z, Zhu Q, Leng Y, Zhang A. Bioorg Med Chem 20 2982-2991 (2012)
  17. Avoidance of the Ames test liability for aryl-amines via computation. McCarren P, Bebernitz GR, Gedeck P, Glowienke S, Grondine MS, Kirman LC, Klickstein J, Schuster HF, Whitehead L. Bioorg Med Chem 19 3173-3182 (2011)
  18. Modulation of glucokinase by glucose, small-molecule activator and glucokinase regulatory protein: steady-state kinetic and cell-based analysis. Bourbonais FJ, Chen J, Huang C, Zhang Y, Pfefferkorn JA, Landro JA. Biochem J 441 881-887 (2012)
  19. S 50131 and S 51434, two novel small molecule glucokinase activators, lack chronic efficacy despite potent acute antihyperglycaemic activity in diabetic mice. De Ceuninck F, Kargar C, Charton Y, Goldstein S, Perron-Sierra F, Ilic C, Caliez A, Rolin JO, Sadlo M, Harley E, Vinson C, Ktorza A. Br J Pharmacol 169 999-1010 (2013)
  20. Novel therapeutics and targets for the treatment of diabetes. Aicher TD, Boyd SA, McVean M, Celeste A. Expert Rev Clin Pharmacol 3 209-229 (2010)
  21. Preclinical PK/PD modeling and human efficacious dose projection for a glucokinase activator in the treatment of diabetes. Zager MG, Kozminski K, Pascual B, Ogilvie KM, Sun S. J Pharmacokinet Pharmacodyn 41 127-139 (2014)
  22. Chronic glucokinase activator treatment at clinically translatable exposures gives durable glucose lowering in two animal models of type 2 diabetes. Baker DJ, Wilkinson GP, Atkinson AM, Jones HB, Coghlan M, Charles AD, Leighton B. Br J Pharmacol 171 1642-1654 (2014)
  23. Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus. Xu J, Lin S, Myers RW, Trujillo ME, Pachanski MJ, Malkani S, Chen HS, Chen Z, Campbell B, Eiermann GJ, Elowe N, Farrer BT, Feng W, Fu Q, Kats-Kagan R, Kavana M, McMasters DR, Mitra K, Tong X, Xu L, Zhang F, Zhang R, Addona GH, Berger JP, Zhang B, Parmee ER. Bioorg Med Chem Lett 27 2063-2068 (2017)
  24. Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes. Qian Y, Corbett WL, Berthel SJ, Choi DS, Dvorozniak MT, Geng W, Gillespie P, Guertin KR, Haynes NE, Kester RF, Mennona FA, Moore D, Racha J, Radinov R, Sarabu R, Scott NR, Grimsby J, Mallalieu NL. ACS Med Chem Lett 4 414-418 (2013)
  25. Structural insight into the glucokinase-ligands interactions. Molecular docking study. Ermakova E. Comput Biol Chem 64 281-296 (2016)
  26. A panel of diverse assays to interrogate the interaction between glucokinase and glucokinase regulatory protein, two vital proteins in human disease. Rees MG, Davis MI, Shen M, Titus S, Raimondo A, Barrett A, Gloyn AL, Collins FS, Simeonov A. PLoS One 9 e89335 (2014)
  27. Discovery and hit-to-lead optimization of novel allosteric glucokinase activators. Lang M, Seifert MH, Wolf KK, Aschenbrenner A, Baumgartner R, Wieber T, Trentinaglia V, Blisse M, Tajima N, Yamashita T, Vitt D, Noda H. Bioorg Med Chem Lett 21 5417-5422 (2011)
  28. Identification of Novel Thiazolo[5,4-b]Pyridine Derivatives as Potent Phosphoinositide 3-Kinase Inhibitors. Xia L, Zhang Y, Zhang J, Lin S, Zhang K, Tian H, Dong Y, Xu H. Molecules 25 E4630 (2020)
  29. Small-Molecule Allosteric Activation of Human Glucokinase in the Absence of Glucose. Bowler JM, Hervert KL, Kearley ML, Miller BG. ACS Med Chem Lett 4 (2013)
  30. Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation. Wang Z, Shi X, Zhang H, Yu L, Cheng Y, Zhang H, Zhang H, Zhou J, Chen J, Shen X, Duan W. Eur J Med Chem 139 128-152 (2017)
  31. Drug discovery alliances in India--indications, targets, and new chemical entities. Differding E. ChemMedChem 9 43-60 (2014)
  32. One-pot synthesis of new (1,3-thiazolo[5,4-b]pyridin-2-yl)benzenediols and their antiproliferative activities against human cancer cell lines. Matysiak J, Karpińska MM, Niewiadomy A, Wietrzyk J, Kłopotowska D. Chem Biodivers 9 48-57 (2012)
  33. Structure based design, synthesis and biological evaluation of amino phosphonate derivatives as human glucokinase activators. Yellapu NK, Kilaru RB, Chamarthi N, Pvgk S, Matcha B. Comput Biol Chem 68 118-130 (2017)
  34. Development of antidiabetic drugs from benzamide derivatives as glucokinase activator: A computational approach. Ali A. Saudi J Biol Sci 29 3313-3325 (2022)
  35. Sabinene: A New Green Solvent Used in the Synthesis of Thiazolo[5,4-b]pyridines by Thermal or Microwave Activation. Messire G, Ferreira V, Caillet E, Bodin L, Auville A, Berteina-Raboin S. Molecules 28 6924 (2023)


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