Synthetic urokinase inhibitors as potential anti-invasive drugs

IDrugs

Volumn 4, Issue 6, 2001, Pages 677-683

  Stürzebecher, Jörg ^a,d   Schweinitz, Andrea ^b   Schmalix, Wolfgang A ^b   Wikström, Peter ^c  

^a Zentrum für Vaskuläre Biologie   (Germany)

^b FRIEDRICH SCHILLER UNIVERSITY JENA   (Germany)

^c Wilex Biotechnology GmbH   (Germany)

^d Pentapharm Ltd   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0003290628     PISSN: 13697056     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (59)

1. Andreasen PA, Kjoller L, Christensen L, Duffy MJ: The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer (1997) 72:1-22. A comprehensive review.
2. Edwards DR, Murphy G: Proteases - invasion and more. Nature (1998)394:527-528.
3. SchmM M, Wilhelm OG, Reuning U, Krüger A, Harbeck N, Lengyel E, Graeff H, Gansbacher B, Kessler H, Burgle M, Stürzebecher J, Sperl S, Magdolen V: The urokinase plasminogen activator system as a novel target for tumour therapy. Fibrinotysis Proteolysis (2000) 14:114-122.
4. This review also reports on other principles for uPA-plasminogen system
5. Dano K, Romer J, Nielsen BS, Bjom S, Pyke C, Rygaard J, Lund LR: Cancer invasion and tissue remodeling - cooperation of protease systems and cell types. APMIS (1999) 107:120-127.
6. Ploug M, Rönne E, Behrendt N, Jensen AL, Blasi F, Dano K: Cellular receptor for urokinase plasminogen activator: CarboxyMerminal processing and membrane anchoring by glycosylphosphatidylinositol. JBiol Chem (1991) 266:1926-1933.
7. Schmitt M, Harbeck N, Thomssen C, Wilhelm O, Magdden V, Reuning U, Ulm K, Hotter H, Jaenicke F, Graeff H: Clinical impact of the plasminogen activation system in tumour invasion and metastasis. Prognostic relevance and target for therapy. Thromb Haemost (1997)78:285-296.
8. Stürzebecher J, Markwardt F: Synthetic inhibitors of serin proteinases. 17. The effect of benzamidine derivatives on the activity of urokinase and the reduction of fibrinolysis. Pharmazie (1978)33:599-602.
9. The first detailed report on uPA inhibitors.
10. Stürzebecher J, Prasa D, Wikström P, Vieweg H: Structure-activity relationships of inhibitors derived from 3-amidinophenylalanine. J
11. Enzyme Inhib (1995) 8:87-99.
12. Sturzebecher J, Prasa D, Hauptmann J, Vieweg H, Wikström P: Structure-activity relationships of potent thrombin inhibitors: piperazides of 3-amidinophenylalanine. J Med Chem (1997) 40:30913099.
13. Stürzebecher J, Vieweg H, Steinmetzer T, Schweinitz A, Stubbs MT, Renatus M, Wikström P: 3-Amidinophenylalanine-based inhibitors of urokinase. Bioorg Med Chem Lett (1999) 9:3147-3152.
14. Structure-activity relationships of the most potent uPA inhibitors of the benzamidine-type are reported.
15. Astedt B, Holmberg L, Wagner G, Richter P, Ploug J: Purification of urokinase by a beta-naphthamidine affinity column. Thromb Haemost (1979) 42:924-928.
16. Nienaber VL, Davidson D, Edalji R, Giranda VL, Klinghofer V, Henkin J, Magdalinos P, Mantel R, Merrick S, Severin JM, Smith RA, Stewart K, Walter K, Wang J, Wendt M, Weitzberg M, Zhao X, Rockway T: Structure-directed discovery of potent non-peptidic inhibitors of human urokinase that access a novel binding subs'rte. Structure (2000) 8:553-563.
17. The paper deals with structure-activity relationships of 8-substituted naphthamidines and offers the respective X-ray structures.
18. Geratz JD, Shaver SR, Tidwell RR: Inhibitory effect of amidinosubsthuted heterocyclic compounds on the amidase activity of plasmin and high and low molecular weight urokinase and on urokinase-induced plasminogen activation. Thromb Res (1981) 24:73-83.
19. Hdwell RR, Geratz JD, Dubovi EJ: Aromatic amidines: Comparison of their ability to block respiratory syncytial virus induced cell fusion and to inhibit plasmin, urokinase, thrombin and trypsin. J
20. Med Chem (1983) 28:294-298.
21. Towle M, Lee A, Maduakor E, Schwartz E, Bridges A, Littiefield B: Inhibition of urokinase by 4-subst'rtuted benzo[6]thiophene-2carboxamidines: An important new class of selective synthetic urokinase inhibitor. Cancer Res (1993) 53:2553-2559.
22. The 'classical'paper concerned with the use of urokinase inhibitors to block cell surface-associated proteolytic activity.
23. Yang H, Henkin J, Kim KH, Gréer J: Selective inhibition of urokinase by substituted phenylguanidines: quantitative structure relationship analyses. J Med Chem (1990) 33:2956-2961.
24. The first report on structure-activity relationships of phenylguanidines as
25. Sperf S'Jacob U, Arroyo de Prada N, Stürzebecher J, Wilhelm O, Bode W, Magdolen V, Huber R, Moroder L (4-Aminomethyl)-phenykjuanidine derivatives as non-peptidic highly selective inhibitors of human urokinase. X-ray crystal structure of an uPATmhibitor complex at 1.8 A resolution. Proc NatlAcad Sei USA (2000) 97:5113-5118.
26. 7776 authors demonstrate binding of a phenylguanidine-derived inhibitor outside the active site ofuPA.
27. Vassalli JO, Belin D: Amiloride selectively inhibits the urokinasetype plasminogen activator. FEBS Lett(1987) 214:187-191.
28. The paper is the first to report the potency of amiloride as a urokinase inhibitor.
29. Bioact Compat Polym (1999) 14:99-121.
30. Nienaber VL, Richardson PL, Klighofer V, Bouska JJ, Giranda VL, Greer J: Discovering novel ligands for macromolecules using X-ray crystallographic screening. Nature Biotechnol (2000) 18:1105-1108.
31. Hajduk PJ, Boyd S, Nettesheim D, Nienaber VL, Severin J, Smhh R, Davidson D, Rockway T, Fesik SW: Identification of novel inhibitors of urokinase via NMR-based screening. J Med Chem (2000) 43:3862-3866.
32. Kettner C, Shaw E: Inactivation of trypsin-like enzymes with peptides of arginine chloromethyl ketone. Methods &izymo/(1981) 80:826-842.
33. Reboud-Ravaux M, Desvages G, Chapeville F: Irreversible inhibition and peptide mapping of urinary plasminogen activator urokinase.
34. FEBS Left (1982) 140:58-62.
35. Markwardt F, Klöcking HP, Stürzebecher J: Thrombolytic effects of acylated urokinase. In: Progress in Fbrinolysis, Vol. VII. Davidson JF, Donati MB, Coccheri S (Eds), Churchill Livingstone, Edinburgh, London, Melbourne, New York (1985):253-257.
36. Tamura S, Weinhouse I, Roberts A, Goldman A, Masukawa K, Anderson S, Cohen C, Bradbury A, Bemardino V, Dixon S, Ma M, Nolan T, Brunck T: Synthesis and biological activity of peptidyl aldehyde urokinase inhibitors. Bioorg Med Chem Lett (2000) 10:983-987.
37. Spraggon G, Phffips C, Nowak UK, Porting CP, Saunders D, Dobson CM, Stuart Dl, Jones E: The crystal structure of the catalytic domain of human urokinase-type plasminogen activator. Structure (1995) 3:681 -691.
38. The paper represents the first analysis of the X-ray structure of uPA.
39. Renatus M, Bode W, Huber R, Stürzebecher J, Stubbs MT: Structural and functional analyses of benzamidine-based inhibitors in complex with trypsin: implications for the inhibition of factor Xa, tPA and urokinase. J Med Chem (1998) 41:5445-5456.
40. Zeslawska E, Schweinitz A, Karcher A, Sondermann P, Sperl S, Stürzebecher J, Jacob U: Crystals of the urokinase type plasminogen activator variant pc-uPA in complex with small molecule inhibitors open the way towards structure-based drug design. J Mol Biol (2000) 301:465-475.
41. The X-ray structures of several uPA-inhibitor complexes are described, which have great utility for inhibitor design.
42. Biol Chem (2000) 275:7239-7248. ...
43. Highly important X-ray structures for structure-based inhibitor design.
44. Billström A, Hartley-Asp B, Lecander l, Batra S, Astedt B: The urokinase inhibitor p-aminobenzamidine inhibits growth of a human prostate tumor in SCID mice. IntJ Cancer(1995) 61:542-547.
45. Rabbani SA, HaraHdas P, Davidson DJ, Henta'n J, Mazar P: Prevention of prostate cancer metastasis in vivo by a novel synthetic inhibitor of urokinase-type plasminogen activator (uPA). Int J Cancer (1995) 63:840-845.
46. B-428 significantly reduced tumor growth and invasiveness at very low doses.
47. Alonso DF, Farias EF, Ladeda V, Davel L, Puricelli L, Joffé EBDK: Effects of synthetic urokinase Inhibitors on local invasion and metastasis in a murine mammary tumor model. Breast Cancer Res Treat (1996) 40:209-223.
48. B-428 and B-623 block invasion and metastasis in a murine mammary tumor model.
49. Swiercz R, Skrzypczak-Jankun E, Merrell MM, Selman SH, Jankun J: Angiostatic activity of synthetic inhibitors of urokinase-type plasminogen activator. Oncol Rep (1999) 6:523-526.
50. References to patent literature
51. This patent claimed the most active uPA inhibitors known up to the time of publication. Synthesis and anti-uPA activity of 232 -naphthamidines are described, 25 of which are stated to inhibit uPA with ICK values < 100 nM.
52. AXYS PHARMACEUTICALS INC (Alien DA, Hataye JM, Hruzewicz WN, Kdesnikov A, Mackman RL, Rai R, Spencer JR, Vemer EJ, Young WB): Proteas inhibKors. WO-00035886 (2000).
53. The invention provides more than 900 5-amidino-benzlmidazotes and 5amidino-indoles; beside inhibitory activity against uPA, some compounds also inhibit Factor Xa.
54. EISAI Co LTD (Bridges A, Schwarte CE, Uttlefield BA): Benzothiophenes and thtenothiophenes and related compounds useful, for example, as urokinase inhibitors. EP-00568289 (1993).
55. 3-DiMENSiONAL PHARMACEUTICALS INC (Illig CR, Subasinghe NL, Hoffmann JB, -Wilson KJ,.-Rudolph MJ): Heteroaryl amidines, methylamidines and gu'anidines as protease inhibitors, in particular as urokinase inhibitors. WO-09940088 (1999).
56. PFIZER INC (Barber CG, Rsh PV, Dickinson RP): Isoquinolines as urokinase inhibitors. WO-09920608 (1999).
57. These 1-guanidino-isoquinoline derivatives seem to be a useful lead for the development of uPA inhibitors; however, limited information on inhibitory potency is given.
58. CORVAS INTERNATIONAL INC (Brunck TK, Tamura SY): Inhibitors of urokinase and blood vessel formation. WO-00005245 (2000).
59. From 53 described tripeptides, 27 compounds inhibit uPA with IC values < 100 nM, although a 30-min preincubation time is necessary.