Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator

Journal of Medicinal Chemistry

Volumn 51, Issue 2, 2008, Pages 183-186

  Frederickson, Martyn ^a   Callaghan, Owen ^a   Chessari, Gianni ^a   Congreve, Miles ^a   Cowan, Suzanna R ^a   Matthews, Julia E ^a   McMenamin, Rachel ^a   Smith, Donna Michelle ^a   Vinković, Mladen ^a   Wallis, Nicola G ^a  

^a ASTEX PHARMACEUTICALS   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

MEXILETINE; MEXILETINE DERIVATIVE; PLASMINOGEN ACTIVATOR INHIBITOR; UNCLASSIFIED DRUG; UROKINASE;

ANIMAL EXPERIMENT; ARTICLE; CRYSTAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG RESEARCH; DRUG SELECTIVITY; ENZYME ACTIVE SITE; ENZYME INHIBITOR INTERACTION; IC 50; NONHUMAN; RAT; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CRYSTALLOGRAPHY, X-RAY; MEXILETINE; MODELS, MOLECULAR; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; URINARY PLASMINOGEN ACTIVATOR;

EID: 38349184176     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm701359z     Document Type: Article

References (24)

1. Duffy, M. J. The urokinase plasminogen activator system: Role in malignancy. Curr. Pharm. Des. 2004, 10, 39-49.
2. Ilies, M. A.; Scozzafava, A.; Supuran, C. T. Therapeutic applications of serine protease inhibitors. Expert Opin. Ther. Pat. 2002, 12, 1181-1214.
3. Ge, Y.; Elghetany, T. Urokinase plasminogen activator receptor (CD87): Something old, something new. Lab. Hematol. 2003, 9, 67-71.
4. Wong, A. P.; Cortez, S. L.; Baricos, W. H. Role of plasmin and gelatinase in extracellular matrix degradation by cultured rat mesangial cells. Am. J. Physiol. Renal Physiol. 1992, 263, 1112-1118.
5. Jean-Claude, J.; Newman, K. M.; Li, H.; Gregory, A. K.; Tilson, M. D. Possible key role for plasmin in the pathogenesis of abdominal aortic aneurysms. Surgery 1994, 116, 472-478.
6. Gveric, D.; Hanemaaijer, R.; Newcombe, J.; van Lent, N. A.; Sier, C. F. M.; Cuzner, M. L. Plasminogen activators in multiple sclerosis legions. Brain 2001, 124, 1978-1988.
7. Schweinitz, A.; Steinmetzer, T.; Banke, I. J.; Arlt, M. J. E.; Stürzebecher, A.; Schuster, O.; Geissler, A.; Giersiefen, H.; Zeslawska, E.; Jacob, U.; Krüger, A.; Stürzebecher, J. Design of novel and selective inhibitors of urokinase-type plasminogen activator with improved pharmacokinetic properties for use as antimetastatic agents. J. Biol. Chem. 2004, 279, 33613-33622.
8. Almholt, K.; Lund, L. R.; Rygaard, J.; Nielsen, B. S.; Danø, K.; Rømer, J.; Johnsen, M. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice. Int. J. Cancer 2005, 113, 522-532.
9. Nienaber, V. L.; Wang, J.; Davidson, D.; Henkin, J. Re-engineering of human urokinase provides a system for structure-based drug design at high resolution and reveals a novel structural subsite. J. Biol. Chem. 2000, 10, 7239-7248.
10. Schweinhorst, A. Direct thrombin inhibitors-a survey of recent developments. Cell. Mol. Life Sci. 2006, 63, 2773-2791.
11. Abbenante, G.; Fairlie, D. P. Protease inhibitors in the clinic. Med. Chem. 2005, 1, 71-104.
12. Hartshorn, M. J.; Murray, C. W.; Cleasby, A.; Frederickson, M.; Tickle, I. J.; Jhoti, H. Fragment-based lead discovery using X-ray crystallography. J. Med. Chem. 2005, 48, 403-413.
13. Nienaber, V. L.; Richardson, P. L.; Klighofer, V.; Bouska, J.; Giranda, V. L.; Greer, J. Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nat. Biotechnol. 2000, 18, 1105-1108.
14. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: A useful metric for lead selection. Drug Discovery Today 2004, 9, 430-431.
15. Hajduk, P. J.; Boyd, S.; Nettesheim, D.; Nienaber, V.; Severin, J.; Smith, R.; Davidson, D.; Rockway, T.; Fesik, S. W. Identification of novel inhibitors of urokinase via NMR-based screening. J. Med. Chem. 2000, 43, 3862-3866.
16. Wendt, M. D.; Rockway, T. W.; Geyer, A.; McClellan, W.; Weitzberg, M.; Zhao, X.; Mantei, R.; Nienaber, V. L.; Stewart, K.; Klinghofer, V.; Giranda, V. Identification of novel binding interactions in the development of potent inhibitors of urokinase. Synthesis, structural analysis, and SAR of N-phenyl amide 6-substitution. J. Med. Chem. 2004, 47, 303-324.
17. Stürzebecher, J.; Vieweg, H.; Steinmetzer, T.; Schweinitz, A.; Stubbs, M. T.; Renatus, M.; Wikström, P. 3-Amidinophenylalanine-based inhibitors of urokinase. Bioorg. Med. Chem. Lett. 1999, 9, 3147-3152.
18. Barber, C. G.; Dickinson, R. P.; Fish, P. V. Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-Isoquinolinylguanidines. Bioorg. Med. Chem. Lett. 2004, 14, 3227-3230.
19. Fish, P. V.; Barber, C. G.; Brown, D. G.; Butt, R.; Collis, M. G.; Dickinson, R. P.; Henry, B. T.; Horne, V. A.; Huggins, J. P.; King, E.; O'Gara, M.; McCleverty, D.; Mcintosh, F.; Phillips, C.; Webster, R. Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7- Sulfonamidoisoquinolinyl)guanidines. J. Med. Chem. 2007, 50, 2341-2351.
20. Hajduk, P. Fragment-based drug design: How big is too big? J. Med. Chem. 2006, 49, 6972-6976.
21. Mackman, R. L.; Katz, B. A.; Breitenbucher, J. G.; Hui, H. C.; Verner, E.; Luong, C.; Liu, L.; Sprengeler, P. A. Exploiting subsite S1 of trypsin-like serine proteases for selectivity: Potent and selective inhibitors of urokinase-type plasminogen activator. J. Med. Chem. 2001, 44, 3856-3871.
22. Monk, J. P.; Brogden, R. N. Mexiletine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias. Drugs 1990, 40, 374-411.
23. Bruncko, M.; McClellan, W. J.; Wendt, M. D.; Sauer, D. R.; Geyer, A.; Dalton, C. R.; Kaminski, M. A.; Weitzberg, M.; Gong, J.; Dellaria, J. F.; Mantei, R.; Zhao, X.; Neinaber, V. L.; Stewart, K.; Klinghofer, V.; Bouska, J.; Rockway, T. W.; Giranda, V. L. Naphthamidine urokinase plasminogen activator inhibitors with improved pharmacokinetic properties. Bioorg. Med. Chem. Lett. 2005, 15, 93-98.
24. Wermuth, C. G. Selective optimization of side activites: Another way for drug discovery. J. Med. Chem. 2004, 47, 1303-1314.