Identification of Novel Binding Interactions in the Development of Potent, Selective 2-Naphthamidine Inhibitors of Urokinase. Synthesis, Structural Analysis, and SAR of N-Phenyl Amide 6-Substitution

Journal of Medicinal Chemistry

Volumn 47, Issue 2, 2004, Pages 303-324

  Wendt, Michael D ^a   Rockway, Todd W ^a   Geyer, Andrew ^a   McClellan, William ^a   Weitzberg, Moshe ^a   Zhao, Xumiao ^a   Mantei, Robert ^a   Nienaber, Vicki L ^a   Stewart, Kent ^a   Klinghofer, Vered ^a   Giranda, Vincent L ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALKYL GROUP; AMIDINE; GUANIDINE; PHENYL GROUP; PLASMINOGEN ACTIVATOR INHIBITOR; UROKINASE;

ARTICLE; CRYSTAL STRUCTURE; DRUG BINDING SITE; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HYDROGEN BOND; HYDROPHILICITY; HYDROPHOBICITY; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

AMIDINES; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NAPHTHALENES; PROTEIN BINDING; SOLVENTS; STRUCTURE-ACTIVITY RELATIONSHIP; URINARY PLASMINOGEN ACTIVATOR;

EID: 9144246951     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0300072     Document Type: Article

References (59)

1. (a) Cook, A. D.; Braine, E. L.; Campbell, I. K.; Hamilton, J. A. Differing roles for urokinase and tissue-type plasminogen activator in collagen-induced arthritis. Am. J. Pathol. 2002, 160, 917-926.
2. (b) Busso, N.; Pleclat, V.; So, A.; Sappino, A.-P. Plasminogen activation in synovial tissues: Differences between normal, osteoarthritis, and rheumatoid arthritis joints. Ann. Rheum. Dis. 1997, 56, 550-557.
3. (a) Noda-Heiny, H.; Daugherty, A.; Sobel, B. E. Augmented urokinase receptor expression in atheroma. Arterioscler. Thromb. Vasc. Biol. 1995, 15, 37-43.
4. (b) Carmeliet, P.; Moons, L.; Lijnen, R.; Baes, M.; Lemaitre, V.; Tipping, P.; Drew, A.; Eeckhout, Y.; Shapiro, S.; Lupu, F.; Collen, D. Urokinase-generated plasmin activates matrix metalloproteinases during aneurism formation. Nature Genet. 1997, 17, 439-444.
5. (c) Falkenberg, M.; Giglio, D.; Bjornheden, T.; Nygren, H.; Risberg, B. Urokinase Plasminogen Activator Colocalizes with CD25+ Cells in Atherosclerotic Vessels. J. Vasc. Res. 1998, 35, 318-324.
6. (d) Preissner, K. T.; Kanse, S. M.; Chavakis, T.; May, A. E.; The Dual Role of the Urokinase Receptor System in Pericellular Proteolysis and Cell Adhesion. Implications for Cardiovascular Function. Basic. Res. Cardiol. 1999, 94, 315-321.
7. Kanse, S. M.; Benzakour, O.; Kanthou, C.; Kost, C.; Lijnen, H. R.; Preissner, K. T. Induction of Vascular SMC Proliferation by Urokinase Indicates a Novel Mechanism of Action in Vasoproliferative Disorders. Arterioscler. Thromb. Vasc. Biol. 1997, 17, 2848-285
8. (a) Rabbani, S. A.; Xing, R. H., Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies. J. Int. Oncol. 1998, 12, 911-920.
9. Bell, W. R. The fibrinolytic system in neoplasia. Sem. Thromb. Hemost. 1996, 22, 459-478.
10. (b) Blasi, F. The Urokinase Receptor. A Cell Surface, Regulated Chemokine. APMIS 1999, 107, 96-101.
11. (a) Andreasen, P. A.; Kjoller, L.; Christensen, L.; Duffy, M. J. The Urokinase-type Plasminogen Activator System in Cancer Metastasis: A Review. Int. J. Cancer 1997, 72, 1-22.
12. (b) Achbarou, A.; Kaiser, S.; Tremblay, G.; Sainte-Marie, L. G.; Brodt, P.; Goltzman, D.; Rabbani, S. A. Cancer Res. 1994, 54, 2372-2377.
13. (c) Duffy, M. J. Urokinase-type plasminogen activator: a potent marker of metastatic potential in human cancers. Biochem. Soc. Trans. 2002, 30, 207-210.
14. Shapiro, R. L.; Duquette, J. G.; Roses, D. F.; Nunes, I.; Harris, M. N.; Kamino, H.; Wilson, E. L.; Rifkin, D. B. Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: Cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals. Cancer Res. 1996, 56, 3597-3604.
15. Bugge, T. H.; Lund, L. R.; Kombrinck, K. K.; Nielsen, B. S.; Holmbäck, K.; Drew, A. F.; Flick, M. J.; Witte, D. P.; Danø, K.; Degen, J. L. Reduced metastasis of Polyoma virus middle T antigen-induced mammary cancer in plasminogen-deficient mice. Oncogene 1998, 16, 3097-3104.
16. Evans, D.; Sloan-Stakleff, K.; Arvan, M.; Guyton, D. Time and dose-dependency of the suppression of pulmonary metastasis of rat mammary cancer by amiloride. Clin. Exp. Metastasis 1998, 16, 353-357.
17. Rabbani, S.; Harakidas, P.; Davidson, D.; Henkin, J.; Mazar, A. Prevention of prostate-cancer metastasis in vivo by a novel synthetic inhibitor of urokinase-type plasminogen activator. Int. J. Cancer 1995, 63, 840-845.
18. Alonso, D. F.; Tejera, A. M.; Farias, E. F.; Bal de Kier Joffe, E.; Bomez, D. E. Inhibition of mammary tumor cell adhesion, migration, and invasion by the selective synthetic urokinase inhibitor B428. Anticancer Res. 1998, 18, 4499-4504.
19. Alonso, D. F.; Farias, E. F.; Ladeda, V.; Davel, L.; Puricelli, L.; Bal de Kier Joffe, E. Effects of synthetic urokinase inhibitors on local invasion and metastasis in a murine mammary tumor model. Breast Cancer Res. Treat. 1996, 40, 209-223.
20. Xing, R. H.; Mazar, A.; Henkin, J.; Rabbani, S. A. Prevention of breast cancer growth, invasion, and metastasis by antiestrogen tamoxifen alone or in combination with urokinase inhibitor B-428. Cancer Res. 1997, 57, 3585-3593.
21. Stürzebecher, J.; Markwardt, F. Synthetische Inhibitoren der Serineproteinasen. Pharmazie 1978, 33, 599-602.
22. Tidwell, R. R.; Geratz, J. D.; Dubovi, E. J. Aromatic amidines. Comparison of their ability to block respiratory syncytial virus induced cell fusion and to inhibit plasmin, urokinase, thrombin, and trypsin. J. Med. Chem. 1983, 26, 294-298.
23. (a) Yang, H.; Henkin, J. Selective Inhibition of Urokinase by Substituted Phenylguanidines: Quantitative Structure-Activity Relationship Analyses. J. Med. Chem. 1990, 33, 2956-2961.
24. (b) Yang, H.; Henkin, J. Competitive Inhibitors of Human Urokinase. Fibrinolysis 1992, 6 (Suppl. 1), 31-34.
25. Vassalli, J.-D.; Belin, D. Amiloride selectively inhibits the urokinase-type plasminogen activator. FEBS Lett. 1987, 214, 187-191.
26. Towle, M. J.; Lee, A.; Maduakor, E. C.; Schwartz, C. E.; Bridges, A. J.; Littlefield, B. A. Inhibition of urokinase by 4-substituted benzo[b]thiophene-2-carboxamidines: An important new class of selective synthetic urokinase inhibitor. Cancer Res. 1993, 53, 2553-2559.
27. Bridges, A. J.; Lee, A.; Schwartz, C. E.; Towle, M. J.; Littlefield, B. A. The synthesis of three 4-substituted benzo[b]thiophene-2-carboxamidines as potent and selective inhibitors of urokinase. Bioorg. Med. Chem. 1993, 1, 403-410.
28. Rudolph, M. J.; Illig, C. R.; Subasinghe, N. L.; Wilson, K. J.; Hoffman, J. B.; Randle, T.; Green, D.; Molloy, C. J.; Soll, R. M.; Lewandowski, F.; Zhang, M.; Bone, R.; Spurlino, J. C.; Deckman, I. C.; Manthey, C.; Sharp, C.; Maguire, D.; Grasberger, B. L.; DesJarlais, R. L.; Zhou, Z. Design and Synthesis of 4,5-Disubstituted-thiophene-2-amidines as Potent Urokinase Inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 491-495.
29. 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.
30. Sperl, S.; Jacob, U.; Arroyo de Prada, N.; Sturzebecher, J.; Wilhelm, O. G.; Bode, W.; Magdolen, V.; Huber, R.; Moroder, L. (4-Aminomethyl)phenylguanidine Derivatives as Nonpeptidic Highly Selective Inhibitors of Human Urokinase. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 5113-5118.
31. (a) Barber, C. G.; Dickinson, R. P.; Horne, V. A. Selective Urokinase-Type Plasminogen Activator (uPA) Inhibitors. Part 1: 2-Pyridinylguanidines. Bioorg. Med. Chem. Lett. 2002, 12, 181-184.
32. (b) Barber, C. G.; Dickinson, R. P. Selective Urokinase-Type Plasminogen Activator (uPA) Inhibitors. Part 2: (3-Substituted-5-halo-2-pyridinyl)guanidines. Bioorg. Med. Chem. Lett. 2002, 12, 185-187.
33. (a) Mackman, R. L.; Hui, H. C.; Breitenbucher, G.; Katz, B. A.; Luong, C.; Martelli, A.; McGee, D.; Radika, K.; Sendzik, M.; Spencer, J. R.; Sprengeler, P. A.; Tario, J.; Verner, E.; Wang, J. 2-(2-Hydroxy-3-alkoxyphenyl)-1H-benzimidazole-5-carboxamidine Derivatives as Potent and Selective Urokinase-type Plasminogen Activator Inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 2019-2022.
34. (b) 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.
35. (c) Verner, E.; Katz, B. A.; Spencer, J. R.; Allen, D.; Hataye, J.; Hruzewicz, W.; Hui, H. C.; Kolesnikov, A.; Li, Y.; Luong, C.; Martelli, A.; Radika, K.; Rai, R.; She, M.; Shrader, W.; Sprengeler, P. A.; Trapp, S.; Wang, J.; Young, W. B.; Mackman, R. A. Development of Serine Protease Inhibitors Displaying a Multicentered Short (<2.3 Å) Hydrogen Bond Binding Mode: Inhibitors of Urokinase-Type Plasminogen Activator and Factor Xa. J. Med. Chem. 2001, 44, 2753-2771.
36. Spencer, J. R.; McGee, D.; Allen, D.; Katz, B. A.; Luong, C.; Sendzik, M.; Squires, N.; Mackman, R. A. 4-Aminoarylguanidine and 4-Aminobenzamidine Derivatives as Potent and Selective Urokinase-type Plasminogen Activator Inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 2023-2026.
37. Nienaber, V. L.; Davidson, D.; Edalji, R.; Girande, V. L.; Klinghofer, V.; Henkin, J.; Magdalinos, P.; Mantel, R.; Merrick, S.; Severin, J. M.; Smith, R. A.; Stewart, K.; Walter, K.; Wang, J.; Wendt, M.; Weitzberg, M.; Zhao, X.; Rockway, T. Structure-directed discovery of potent nonpeptidic inhibitors of human urokinase that access a novel binding subsite. Structure 2000, 8, 553-563.
38. Klinghofer, V.; Stewart, K.; McGonigal, T.; Smith, R.; Sarthy, A.; Nienaber, V.; Butler, C.; Dorwin, S.; Richardson, P.; Weitzberg, M.; Wendt, M.; Rockway, T.; Zhao, X.; Hulkower, K. I.; Giranda, V. L. Species Specificity of Amidine-Based Urokinase Inhibitors. Biochemistry 2001, 40, 9125-9131.
39. Campagna, F.; Carotti, A.; Casini, G. A Convenient Synthesis of Nitriles From Primary Amides Under Mild Conditions. Tetrahedron Lett. 1977, 18, 1813-1816.
40. Boere, R. T.; Oakley, R. T.; Reed, R. W. Preparation of N,N,N′-tris(trimethylsilyl)amidines; a convenient route to unsubstituted amidines. J. Orgmet. Chem. 1987, 331, 161-167.
41. Roger, R.; Neilson, D. G. The Chemistry of Imidates. Chem. Rev. 1961, 61, 179-211.
42. Bredereck, H.; Gompper, R.; Seiz, H. Umsetzung Des Thioformamids Mit Halogenverbindungen. Chem. Ber. 1957, 90, 1837-1843.
43. Testaferri, L.; Tiecco, M.; Tingoli, M.; Chianelli, D.; Montanucci, M. Simple Syntheses of Aryl Alkyl Thioethers and of Aromatic Thiols from Unactivated Aryl Halides and Efficient Methods for Selective Dealkylation of Aryl Alkyl Ethers and Thioethers. Synthesis 1983, 751-755.
44. Gray, N. M.; Cheng, B. K.; Mick, S. J.; Lair, C. M.; Contreras, P. C. Phencyclidine-like Effects of Tetrahydroisoquinolines and Related Compounds. J. Med. Chem. 1989, 32, 1242-1248.
45. Larsen, R. D.; Reamer, R. A.; Corley, E. G.; Davis, P.; Grabowski, E. J. J.; Reider, P. J.; Shinkai, I. A Modified Bischler-Napieralski Procedure for the Synthesis of 3-Aryl-3,4-dihydroisoquinolines. J. Org. Chem. 1991, 56, 6034-6038.
46. Quallich, G. J.; Makowski, T. W.; Sanders, A. F.; Urban, F. J.; Vazquez, E. Synthesis of 1,2,3,4-Tetrahydroisoquinolines Containing Electron-Withdrawing Groups. J. Org. Chem. 1998, 63, 4116-4119.
47. Park, K. K.; Oh, C. H.; Joung, W. K. Sodium Dithionite Reduction of Nitroarenes Using Viologen as an Electron Phase-Transfer Catalyst. Tetrahedron Lett. 1993, 34, 7445-7446.
48. Lemaire-Audoire, S.; Savignac, M.; Genet, J. P. Selective Deprotection of Allylamines using Palladium. Tetrahedron Lett. 1995, 36, 1267-1270.
49. (a) Maignan, S.; Mikol, V. The Use of 3D Structural Data in the Design of Specific Factor Xa Inhibitors. Curr. Top. Med. Chem. 2001, 1, 161-174.
50. (b) Rai, R.; Sprengeler, P. A.; Elrod, K. C.; Young, W. B. Perspectives on Factor Xa Inhibition. Curr. Med. Chem. 2001, 8, 101-119.
51. (c) Coburn, C. A. Small-molecule Direct Thrombin Inhibitors: 1997-2000. Expert. Opin. Ther. Pat. 2001, 11, 721-738.
52. (d) Sanderson, P. E. J. Anticoagulants: Inhibitors of Thrombin and Factor Xa. Ann. Rep. Med. Chem. 2001, 36, 79-88.
53. Spraggon, G.; Phillips, C.; Nowak, U. K.; Ponting, C. P.; Saunders, D.; Dobson, C. M.; Stuart, D. I.; Jones, E. Y. The crystal structure of the catalytic domain of human urokinase-type plasminogen activator. Structure 1995, 3, 681-691.
54. Renatus, M.; Bode, W.; Huber, R.; Stürzebecher, J.; Stubbs, M. T. 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.
55. (a) Katz, B. A.; Mackman, R.; Luong, C.; Radika, K.; Martelli, A.; Sprengeler, P. A.; Wang, J.; Chan, H.; Wong, L. Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator. Chem. Biol. 2000, 7, 299-312.
56. (b) Katz, B. A.; Sprengeler, P. A.; Luong, C.; Verner, E.; Elrod, K.; Kirtley, M.; Janc, J.; Spencer, J. R.; Breitenbucher, J. G.; Hui, H.; McGee, D. ; Allen, D.; Martelli, A.; Mackman, R. L. Engineering inhibitors highly selective for the S1 sites of Ser190 trypsin-like serine protease crug targets. Chem. Biol. 2001, 8, 1107-1121.
57. Wendt, M. D., unpublished results.
58. Dunitz, J. D. The Entropic Cost of Bound Water in Crystals and Biomolecules. Science 1994, 264, 670.
59. Nienaber, V.; Wang, J.; Davidson, D.; Henkin, J. Reengineering of human urokinase provides a system for structure-based drug design at high resolution and reveals a novel binding subsite. J. Biol. Chem. 2000, 275, 7239-7248.