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Identification, synthesis, and characterization of new glycogen phosphorylase inhibitors binding to the allosteric AMP site.

Kristiansen M, Andersen B, Iversen LF, Westergaard N
J Med Chem 47 3537-45 (2004)
Cited: 27 times
EuropePMC logo PMID: 15214781

Abstract

Inhibition of glycogen phosphorylase (GP) has attracted considerable attention during the last five to 10 years as a means of treating the elevated hepatic glucose production seen in patients with type 2 diabetes. Several different GP inhibitors binding to various binding sites of the GP enzyme have been reported in the literature. In this paper we report on a novel class of compounds that have been identified as potent GP inhibitors. Their synthesis, mode of binding to the allosteric AMP site as well as in vitro data on GP inhibition are shown. The most potent inhibitor was found to be 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid (4j) with an IC(50) value of 74 nM. This compound together with a closely related analogue was further characterized by enzyme kinetics and in primary rat hepatocytes.

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  1. Ligand-binding site prediction of proteins based on known fragment-fragment interactions. Kasahara K, Kinoshita K, Takagi T. Bioinformatics 26 1493-1499 (2010)
  2. FTMove: A Web Server for Detection and Analysis of Cryptic and Allosteric Binding Sites by Mapping Multiple Protein Structures. Egbert M, Jones G, Collins MR, Kozakov D, Vajda S. J Mol Biol 434 167587 (2022)


Reviews citing this publication (6)

  1. New hepatic targets for glycaemic control in diabetes. Agius L. Best Pract. Res. Clin. Endocrinol. Metab. 21 587-605 (2007)
  2. Expanding the number of 'druggable' targets: non-enzymes and protein-protein interactions. Makley LN, Gestwicki JE. Chem Biol Drug Des 81 22-32 (2013)
  3. Recent and emerging anti-diabetes targets. Mohler ML, He Y, Wu Z, Hwang DJ, Miller DD. Med Res Rev 29 125-195 (2009)
  4. Glycogen metabolism has a key role in the cancer microenvironment and provides new targets for cancer therapy. Zois CE, Harris AL. J. Mol. Med. 94 137-154 (2016)
  5. Glycogen metabolism in cancer. Zois CE, Favaro E, Harris AL. Biochem. Pharmacol. 92 3-11 (2014)
  6. Synthetic strategies, SAR studies, and computer modeling of indole 2 and 3-carboxamides as the strong enzyme inhibitors: a review. Chehardoli G, Bahmani A. Mol Divers 25 535-550 (2021)

Articles citing this publication (19)

  1. Bioactivity of glycogen phosphorylase inhibitors that bind to the purine nucleoside site. Hampson LJ, Arden C, Agius L, Ganotidis M, Kosmopoulou MN, Tiraidis C, Elemes Y, Sakarellos C, Leonidas DD, Oikonomakos NG. Bioorg. Med. Chem. 14 7835-7845 (2006)
  2. Novel thienopyrrole glycogen phosphorylase inhibitors: synthesis, in vitro SAR and crystallographic studies. Whittamore PR, Addie MS, Bennett SN, Birch AM, Butters M, Godfrey L, Kenny PW, Morley AD, Murray PM, Oikonomakos NG, Otterbein LR, Pannifer AD, Parker JS, Readman K, Siedlecki PS, Schofield P, Stocker A, Taylor MJ, Townsend LA, Whalley DP, Whitehouse J. Bioorg. Med. Chem. Lett. 16 5567-5571 (2006)
  3. Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase. Anagnostou E, Kosmopoulou MN, Chrysina ED, Leonidas DD, Hadjiloi T, Tiraidis C, Zographos SE, Györgydeák Z, Somsák L, Docsa T, Gergely P, Kolisis FN, Oikonomakos NG. Bioorg. Med. Chem. 14 181-189 (2006)
  4. The crystal structure of human muscle glycogen phosphorylase a with bound glucose and AMP: an intermediate conformation with T-state and R-state features. Lukacs CM, Oikonomakos NG, Crowther RL, Hong LN, Kammlott RU, Levin W, Li S, Liu CM, Lucas-McGady D, Pietranico S, Reik L. Proteins 63 1123-1126 (2006)
  5. Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy. Thomson SA, Banker P, Bickett DM, Boucheron JA, Carter HL, Clancy DC, Cooper JP, Dickerson SH, Garrido DM, Nolte RT, Peat AJ, Sheckler LR, Sparks SM, Tavares FX, Wang L, Wang TY, Weiel JE. Bioorg. Med. Chem. Lett. 19 1177-1182 (2009)
  6. Binding of beta-D-glucopyranosyl bismethoxyphosphoramidate to glycogen phosphorylase b: kinetic and crystallographic studies. Chrysina ED, Kosmopoulou MN, Kardakaris R, Bischler N, Leonidas DD, Kannan T, Loganathan D, Oikonomakos NG. Bioorg. Med. Chem. 13 765-772 (2005)
  7. Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs. Oikonomakos NG, Kosmopoulou MN, Chrysina ED, Leonidas DD, Kostas ID, Wendt KU, Klabunde T, Defossa E. Protein Sci. 14 1760-1771 (2005)
  8. Synthesis of 5-chloro-N-aryl-1H-indole-2-carboxamide derivatives as inhibitors of human liver glycogen phosphorylase a. Onda K, Suzuki T, Shiraki R, Yonetoku Y, Negoro K, Momose K, Katayama N, Orita M, Yamaguchi T, Ohta M, Tsukamoto S. Bioorg. Med. Chem. 16 5452-5464 (2008)
  9. Increased potency and efficacy of combined phosphorylase inactivation and glucokinase activation in control of hepatocyte glycogen metabolism. Hampson LJ, Agius L. Diabetes 54 617-623 (2005)
  10. Benzamide derivatives as dual-action hypoglycemic agents that inhibit glycogen phosphorylase and activate glucokinase. Zhang L, Li H, Zhu Q, Liu J, Chen L, Leng Y, Jiang H, Liu H. Bioorg. Med. Chem. 17 7301-7312 (2009)
  11. Discovering benzamide derivatives as glycogen phosphorylase inhibitors and their binding site at the enzyme. Chen L, Li H, Liu J, Zhang L, Liu H, Jiang H. Bioorg. Med. Chem. 15 6763-6774 (2007)
  12. FR258900, a potential anti-hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase. Tiraidis C, Alexacou KM, Zographos SE, Leonidas DD, Gimisis T, Oikonomakos NG. Protein Sci. 16 1773-1782 (2007)
  13. Design, synthesis, and pharmacological evaluation of N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives as potent glycogen phosphorylase inhibitors. Onda K, Shiraki R, Ogiyama T, Yokoyama K, Momose K, Katayama N, Orita M, Yamaguchi T, Furutani M, Hamada N, Takeuchi M, Okada M, Ohta M, Tsukamoto S. Bioorg. Med. Chem. 16 10001-10012 (2008)
  14. Structural investigations of anthranilimide derivatives by CoMFA and CoMSIA 3D-QSAR studies reveal novel insight into their structures toward glycogen phosphorylase inhibition. Saqib U, Kumar B, Siddiqi MI. SAR QSAR Environ Res 22 411-449 (2011)
  15. Synthesis and structure-activity relationships of 3-phenyl-2-propenamides as inhibitors of glycogen phosphorylase a. Li YH, Coppo FT, Evans KA, Graybill TL, Patel M, Gale J, Li H, Tavares F, Thomson SA. Bioorg. Med. Chem. Lett. 16 5892-5896 (2006)
  16. Binding of oxalyl derivatives of beta-d-glucopyranosylamine to muscle glycogen phosphorylase b. Hadjiloi T, Tiraidis C, Chrysina ED, Leonidas DD, Oikonomakos NG, Tsipos P, Gimisis T. Bioorg. Med. Chem. 14 3872-3882 (2006)
  17. Modeling aided design of potent glycogen phosphorylase inhibitors. Deng Q, Lu Z, Bohn J, Ellsworth KP, Myers RW, Geissler WM, Harris G, Willoughby CA, Chapman K, McKeever B, Mosley R. J. Mol. Graph. Model. 23 457-464 (2005)
  18. Synthesis and pharmacological evaluation of bis-3-(3,4-dichlorophenyl)acrylamide derivatives as glycogen phosphorylase inhibitors. Onda K, Shiraki R, Yonetoku Y, Momose K, Katayama N, Orita M, Yamaguchi T, Ohta M, Tsukamoto S. Bioorg. Med. Chem. 16 8627-8634 (2008)
  19. Extrapolative prediction using physically-based QSAR. Cleves AE, Jain AN. J. Comput. Aided Mol. Des. 30 127-152 (2016)


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