Recent Updates on Glucokinase Activators and Glucokinase Regulatory Protein Disrupters for the Treatment of Type 2 Diabetes Mellitus

Author(s): Aditi Kaushik* , Manish Kaushik .

Journal Name: Current Diabetes Reviews

Volume 15 , Issue 3 , 2019

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Abstract:

Introduction: The impairment of glucose metabolism leads to hyperglycemia and type-2 diabetes mellitus. Glucokinase enzyme is the key regulator of glucose homeostasis that catalyzes the conversion of glucose to glucose-6-phosphate in liver and pancreatic cells. In hepatocytes, GK controls the glucose uptake and glycogen synthesis. The action of liver GK is controlled by Glucokinase Regulatory Protein (GKRP) partially. In fasting conditions the GKRP binds with GK and inactivate it from carbohydrate metabolism and serve as new target for treatment of diabetes mellitus. However, the GK activators as potential antidiabetic agents but results in increased risks of hypoglycemia.

Conclusion: The allosteric inhibitors of the GK-GKRP interaction are coming as alternative agents that can mitigate the risk associated with GK activators. This review discusses the recent advances and current status of potential molecules targeted to GK activators and GK-GKRP disrupters.

Keywords: Type 2 diabetes mellitus, Glucokinase, Glucokinase regulatory protein, allosteric regulators, glucokinase activators, glucose concentration.

[1]
Kumar P, Clark M. Clinical Medicine. 7th ed. Elsevier Saunders London 2009.
[2]
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183-97.
[3]
World Health Organization Study Group Diabetes Mellitus: WHO Technical Report, Series 727. Geneva World Health Organization. 1985.
[4]
DeFronzo RA, Ferrannini E, Keen H, Zimmet P. International Textbook of Diabetes Mellitus. 3rd ed. John Wiley & Sons Ltd.Chichester 2004.
[5]
Guyton AC, Hall JE. Textbook of Medical Physiology. 11th ed. Elsevier Saunders : London, 2006.
[6]
Ripsin CM, Kang H, Urban RJ. Management of blood glucose in type 2 diabetes mellitus. Am Fam Physician 2009; 79(1): 29-36.
[7]
Korytkowski MT. Sulfonylurea treatment of type 2 diabetes mellitus: focus on glimepiride. Pharmacotherapy 2004; 24(5): 606-20.
[8]
Jennifer JC, Johannes BP. Recent advances in therapeutic approaches for type 2 diabetes. Annu Rep Med Chem 2005; 8: 168-81.
[9]
Rafiq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley AT. Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations. Diabetes Care 2008; 31(2): 204-9.
[10]
Bailey CJ. Biguanides and NIDDM. Diabetes Care 1992; 15(6): 755-72.
[11]
Pittas AG, Greenberg AS. Thiazolidienediones in the treatment of type 2 diabetes. Expert Opin Pharmacother 2002; 3(5): 529-40.
[12]
Naji JMA, Sarabu R, Grimsby J. Glucokinase activators for diabetes therapy. Diabetes Care 2011; 34(Suppl. 2): S236-43.
[13]
Vinuela E, Salas M, Sols A. Glucokinase and hexokinase in liver in relation to glycogen synthesis. J Biol Chem 1963; 38(3): 1175-7.
[14]
Matschinsky FM, Ellerman JE. Metabolism of glucose in the islets of Langerhans. J Biol Chem 1968; 243(10): 2730-6.
[15]
Matschinsky FM, Magnuson MA, Zelent D, et al. The network of glucokinase expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes 2006; 55: 1-12.
[16]
Priyadarsini RL, Namratha JR, Reddy DRS. Glucokinase activators: A glucose sensor role in pancreatic islets and hepatocyte. Int J Pharm Pharm Sci 2012; 4(2): 81-7.
[17]
Meglasson MD, Matschinsky FM. New perspectives on pancreatic islet glucokinase. Am J Physiol 1984; 246: E1-E13.
[18]
Iynedjian PB. Molecular physiology of mammalian glucokinase. Cell Mol Life Sci 2009; 66(1): 27-42.
[19]
Massa M, Gagliardino JJ, Francini F. Liver glucokinase: An overview on the regulatory mechanisms of its activity. IUBMB Life 2011; 63(1): 1-6.
[20]
Pal M. Recent advances in glucokinase activators for the treatment of type 2 diabetes. Drug Discov Today 2009; 14(15-16): 784-92.
[21]
Tahrani AA, Bailey CJ, Prato SD, Barnett AH. Managementof type 2 diabetes: new and future developments in treatment. The Lancet 2011; 378(9786): 182-97.
[22]
Matschinsky FM. Accessing the potential of glucokinase activators in diabetes therapy. Nature 2009; 8: 399-419.
[23]
Nakamura A, Terauchi Y. Present status of clinical development of glucokinase activators. J Diabetes Investig 2015; 6(2): 124-32.
[24]
Matschinsky FM. Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics. Diabetes 2002; 51(Suppl. 3): S394-404.
[25]
Grimsby J, Sarabu R, Corbett WL, et al. Allosteric activators of glucokinase: potential role in diabetes therapy. Science 2003; 301: 370-3.
[26]
Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y. Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure (Camb) 2004; 12: 429-38.
[27]
Ashton KS, Andrews KL, Bryan MC. Small molecule disruptors of the glucokinase–glucokinase regulatory protein interaction: 1. discovery of a novel tool compound for in vivo proof-of-concept. J Med Chem 2014; 57(2): 309-24.
[28]
Baltrusch S, Tiedge M. Glucokinase regulatory network in pancreatic β-cells and liver. Diabetes 2006; 55: S55-64.
[29]
Grewal AS, Sekhon BS, Lather V. Recent updates on glucokinase activators for the treatment of type 2 Diabetes Mellitus. Mini Rev Med Chem 2014; 14(7): 585-602.
[30]
Heusera S, Barretta DG, Berga M, et al. Synthesis of novel cyclopropylic sulfones and sulfonamides acting as glucokinase activators. Tetrahedron Lett 2006; 47(16): 2675-8.
[31]
Iino T, Sasaki Y, Bamba M, et al. Discovery and structure-activity relationships of a novel class of quinazoline glucokinase activators. Bioorg Med Chem Lett 2009; 19(19): 5531-8.
[32]
Sidduri A, Grimsby JS, Corbett WL. 2,3-Disubstituted acrylamides as potent glucokinase activators. Bioorg Med Chem Lett 2010; 20(19): 5673-6.
[33]
Lang M, Seifert MH, Wolf KK. Discovery and hit-to-lead optimization of novel allosteric glucokinase activators. Bioorg Med Chem Lett 2011; 21(18): 5417-22.
[34]
Lloyd DJ, St. Jean DJ Jr, Kurzeja RJM. Antidiabetic effects of glucokinase regulatory protein small molecule disruptors. Nature 2013; 504: 437-40.
[35]
Pfefferkorn JA, Guzman P, Litchfield RJ, et al. Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propana-mido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus. J Med Chem 2012; 55: 1318-33.
[36]
Chen K, Michelsen K, Kurzeja RJM, et al. Discovery of small-molecule glucokinase regulatory protein modulators that restore glucokinase activity. J Biomol Screen 2014; 19(7): 1014-23.
[37]
Du X, Hinklin RJ, Xiong Y, et al. C-5-alkyl-2-methylurea-subsituted pyridines as a new class of glucokinase activators. ACS Med Chem Lett 2014; 5: 1284-9.
[38]
Kohn TJ, Du X, Lai SJ, et al. 5-Alkyl-2-urea-Substituted Pyridines: Identification of Efficacious Glucokinase Activators with Improved Properties. ACS Med Chem Lett 2016; 7: 666-70.
[39]
Park K, Lee BM, Hyun KH, Han T, Lee DH, Choi HH. Design and synthesis of acetylenyl benzamide derivatives as novel glucokinase activators for the treatment of T2DM. ACS Med Chem Lett 2015; 6: 296-301.
[40]
Park K, Leeb BM, Hyun KH, et al. Discovery of 3-(4-methanesulphonylphenoxy)-N-[1-(2-methoxyethoxymethyl)-1H-pyrazole-3-yl]-5-(3-methylpyridin-2-yl)-benzamide as a novel glucokinase activator (GKA) for the treatment of type 2 diabetes mellitus. Bioorg Med Chem 2014; 22: 2280-93.
[41]
Dransfield PJ, Pattaropong V, Lai S, et al. Novel series of potent glucokinase activators leading to the discovery of AM-2394. ACS Med Chem Lett 2016; 7: 714-8.
[42]
Paczal A, Lint B, Wéber C, et al. Structure−activity relationship of azaindole-based glucokinase activators. J Med Chem 2016; 59: 687-706.
[43]
Xu J, Lin S, Myers RW, et al. Novel, highly potent systemic glucokinase activators for the treatment of Type 2 Diabetes Mellitus. Bioorg Med Chem Lett 2017; 27: 2069-73.
[44]
Yellapu NK, Kilaru RB, Chamarthic N. PVGK S, Matcha B. Structure based design, synthesis and biological evaluation of amino phosphonate derivatives as human glucokinase activators. Comput Biol Chem 2017; 68: 118-30.
[45]
Martinez JA, Xiao Q, Zakarian A, Miller BG. Antidiabetic disrupters of the glucokinase-glucokinase regulatory protein complex recognize a coulombic interface. Biochemistry 2017; 56(24): 3150-7.
[46]
Al-Hasani H, Tschop MH, Cushman SW. Two birds with one stone: novel glucokinase activator stimulates glucose-induced pancreatic insulin secretion and augments hepatic glucose metabolism. Mol Interv 2003; 3(7): 367-70.
[47]
Ashton KS, Andrews KL, Bryan MC. Small molecule disruptors of the glucokinase–glucokinase regulatory protein interaction: 1. discovery of a novel tool compound for in vivo proof-of-concept. J Med Chem 2014; 57(2): 309-24.
[48]
St. Jean Jr D.J., Ashton KS, Bartberger MD, et al. Small molecule disruptors of the glucokinase−glucokinase regulatory protein interaction: 2. leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles. J Med Chem 2014; 57: 325-38.
[49]
Hong FT. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 4. exploration of a novel binding pocket. J Med Chem 2014; 57: 5949-64.
[50]
Tamayo NA, Norman MH, Bartberger MD, et al. Small molecule disruptors of the glucokinase– glucokinase regulatory protein interaction: 5. a novel aryl sulfone series, optimization through conformational analysis. J Med Chem 2015; 58(11): 4462-82.
[51]
Pennington LD, Bartberger MD, Croghan MD, et al. Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase−Glucokinase Regulatory Protein (GK−GKRP) Binding: Strategic Use of a N → S (nN → σ*S−X) Interaction for Conformational Constraint. J Med Chem 2015; 58: 9663-79.
[52]
Deshpande AM, Bhuniya D, De S, et al. Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia. Eur J Med Chem 2017; 133: 268-86.
[53]
Xu J, Lin S, Myers RW, et al. Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus. Bioorg Med Chem Lett 2017; 27: 2063-8.


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Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [205 - 212]
Pages: 8
DOI: 10.2174/1573399814666180724100749
Price: $58

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