Orally active fibrinogen receptor antagonists. 2. Amidoximes as prodrugs of amidines

Journal of Medicinal Chemistry

Volumn 39, Issue 16, 1996, Pages 3139-3147

  Weller, Thomas ^b   Alig, Leo ^b   Beresini, Maureen ^a   Blackburn, Brent ^a   Bunting, Stuart ^a   Hadváry, Paul ^b   Müller, Marianne Hürzeler ^b   Knopp, Dietmar ^b   Levet Trafit, Bernard ^b   Lipari, M Terry ^a   Modi, Nishit B ^a   Müller, Marcel ^b   Refino, Canio J ^a   Schmitt, Monique ^b   Schönholzer, Peter ^b   Weiss, Sabine ^b   Steiner, Beat ^b  

^a GENENTECH INC   (United States)

^b F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDINE; FIBRINOGEN RECEPTOR ANTAGONIST; LAMIFIBAN; PRODRUG; RO 44 3888; SIBRAFIBAN; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTERY THROMBOSIS; ARTICLE; ATHEROSCLEROTIC PLAQUE; COMPETITIVE INHIBITION; CONTROLLED STUDY; CROSS LINKING; FIBRINOLYSIS; HEART MUSCLE ISCHEMIA; HEMOSTASIS; HIGH RISK POPULATION; NONHUMAN; ORAL DRUG ADMINISTRATION; SECONDARY PREVENTION; SHEAR STRESS; THROMBOGENESIS;

ACETATES; ADMINISTRATION, ORAL; AMIDINES; ANIMALS; ANTICOAGULANTS; DOGS; MACACA MULATTA; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; MICE; MOLECULAR STRUCTURE; OXIMES; PIPERIDINES; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX; PRODRUGS; RATS; TYROSINE;

EID: 9344236530     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9509298     Document Type: Article

References (65)

1. Turitto, V. T.; Baumgartner, H. R. Platelet-Surface Interactions. In Hemostasis and Thrombosis, Basic Principles and Clinical Practice; Colman, R. W., Hirsh, J., Marder, V. J., Salzmann, E. W., Eds.; J. B. Lippincott Co.: Philadelphia, 1982; pp 364-379.
2. Leonard, E. F.; Turitto, V. T.; Vroman, L. Blood in contact with natural and artificial surfaces.Ann. N.Y. Acad. Sci. 1987, 516, 1-688.
3. Verstraete, M.; Zoldhelyi, P. Novel Antithrombotic Drugs in Development. Drugs 1995, 49, 856-884.
4. Scharf, R. E.; Harker, L. A. Thrombosis and Atherosclerosis: Regulatory Role of Interactions Among Blood Components and Endothelium. Blut 1987, 55, 131-144.
5. Ip, J. P.; Stein, B.; Fuster, V.; Badimon, L. Antithrombotic therapy in cardiovascular diseases. Ann. N.Y. Acad. Sci. 1991, 614, 289-311.
6. Badimon, L.; Badimon, J. J.; Chesebro, J. H.; Fuster, V. von Willebrand Factor and Cardiovascular Disease. Thromb. Haemostasis 1993, 70, 111-118.
7. Meyer, D.; Fressinaud, E.; Sakariassen, K. S.; Baumgartner, H. R.; Girma, J. P. Role of von Willebrand Factor in Platelet Vessel-Wall Interactions. Ann. N.Y. Acad. Sci. 1987, 509, 118-130.
8. Savage, B.; Shattil, S. J.; Ruggeri, Z. M. Modulation of Platelet Function through Adhesion Receptors. J. Biol. Chem. 1992, 267, 11300-11306.
9. Phillips, D. R.; Charo, I. F.; Parise, L. V.; Fitzgerald, L. A. The Platelet Membrane Glycoprotein IIb-IIIa Complex. Blood 1988, 71, 831-843.
10. Kroll, M. H.; Schafer, A. I. Biochemical Mechanisms of Platelet Activation. Blood 1989, 74, 1181-1185.
11. Hawiger, J. Formation and Regulation of Platelet and Fibrin Hemostatic Plug. Hum. Pathol. 1987, 18, 111-122.
12. Lüscher, E. F.; Weber, S. The formation of the hemostatic plug. Thromb. Haemostasis 1993, 70, 234-237.
13. Coutré, S.; Leung, L. Novel antithrombotic therapeutics targeted against platelet glycoprotein IIb/IIIa. Annu. Rev. Med. 1995, 46, 257-265.
14. Coller, B. S. Platelets and Thrombolytic Therapy. N. Engl. J. Med. 1990, 322, 33-42.
15. Ezratty, A. M.; Loscalzo, J. New approaches to antiplatelet therapy. Blood Coagulation Fibrinolysis 1991, 2, 317-327.
16. Das, J.; Hall, S. E. Platelet Aggregation Inhibitors. Curr. Opin. Ther. Patents 1991, 1, 221-240.
17. Jakubowski, J. A.; Smith, G. F.; Sall, D. J. Future Antithrombotic Therapy. Annu. Rep. Med. Chem. 1992, 27, 99-108.
18. The EPIC investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N. Engl. J. Med. 1994, 330, 956-961.
19. Topol, E. J.; Califf, R. M.; Weisman, H. F.; Anderson, K.; Wang, A.; Willerson, J. T. Six-month follow-up after acute phase platelet IIb/IIIa integrin blockade in the EPIC trial: reduction in need for revascularization procedures. J. Am. Coll. Cardiol. 1994, 23, 60A.
20. Blackburn, B. K.; Gadek, T. R. Glycoprotein IIb/IIIa antagonists. Annu. Rep. Med. Chem. 1993, 28, 79-88.
21. Kouns, W. C.; Roux, S.; Steiner, B. Human platelet GP IIb-IIIa receptor blockade as a therapeutic strategy. Curr. Opin. Invest. Drugs 1993, 2, 475-494.
22. Cook, N. S.; Kottirsch, G.; Zerwes, H.-G. Platelet glycoprotein IIb/IIIa antagonists. Drugs Future 1994, 19, 135-159.
23. Weller, T.; Alig, L.; Hürzeler Müller, M.; Kouns, W. C.; Steiner, B. Fibrinogen receptor antagonists - a novel class of promising antithrombotics. Drugs of the Future 1994, 19, 461-476.
24. Zablocki, J. A.; Nicholson, N. S.; Feigen, L. P. Fibrinogen receptor antagonists. Exp. Opin. Invest. Drugs 1994, 3, 437-448.
25. Cox, D. Integrins and cardiovascular disease. Exp. Opin. Invest. Drugs 1995, 4, 413-423.
26. Egbertson, M. S.; Chang, C. T.-C.; Duggan, M. E.; Gould, R. J.; Halczenko, W.; Hartman, G. D.; Laswell, W. L.; Lynch, J. J., Jr.; Lynch, R. J.; Manno, P. D.; Naylor, A. M.; Prugh, J. D.; Ramjit, D. R.; Sitko, G. R.; Smith, R. S.; Turchi, L. M.; Zhang, G. Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-Asp. J. Med. Chem. 1994, 37, 2537-2551.
27. Naylor, A. M.; Egbertson, M. S.; Vassallo, L. M.; Birchenough, L. A.; Zhang, G. X.; Gould, R. J.; Hartman, G. D. Non-Peptide Fibrinogen Receptor Antagonists. 4. Proposed Three-Dimensional Requirements in Centrally Constrained Inhibitors. Bioorg. Med. Chem. Lett. 1994, 4, 1841-1846.
28. Askew, B. C.; McIntyre, C. J.; Hunt, C. A.; Claremon, D. A.; Gould, R. J.; Lynch, R. J.; Armstrong, D. J. Non-Peptide Glycoprotein IIb/IIIa Inhibitors. 6. Design and Synthesis of Rigid, Centrally Constrained Non-Peptide Fibrinogen Receptor Antagonists.Bioorg. Med. Chem. Lett. 1995, 5, 475-480.
29. Ku, T. W.; Miller, W. H.; Bondinell, W. E.; Erhard, K. F.; Keenan, R. M.; Nichols, A. J.; Peishoff, C. E.; Samanen, J. M.; Wong, A. S.; Huffman, W. F. Potent Non-peptide Fibrinogen Receptor Antagonists Which Present an Alternative Pharmacophore. J. Med. Chem. 1995, 38, 9-12.
30. Cox, D. Targets in Integrin Research. Drug News Perspect. 1995, 8, 197-205.
31. Ojima, I.; Chakravarty, S.; Dong, Q. Antithrombotic Agents: From RGD to Peptide Mimetics. Bioorg. Med. Chem. 1995, 3, 337-360.
32. Stadel, J. M.; Nichols, A. J.; Bertolini, D. R.; Samanen, J. M. Therapeutic Potential of Integrin Antagonists. In Integrins; Cheresh, D. A., Mecham, R. P., Eds.; Academic Press, Inc.: San Diego, 1994; pp 237-271.
33. Ruoslahti, E. Integrins. J. Clin. Invest. 1991, 87, 1-5.
34. Tcheng, J. E.; Ellis, S. G.; Kleiman, N. S.; Harrington, R. A.; Mick, M. J.; Navetta, F. I.; Worley, S.; Smith, J. E.; Kereiakes, D. J.; Kitt, M. M.; Miller, J. A.; Sigmon, K. N.; Califf, R. M.; Topol, E. J. Outcome of Patients Treated with the GP IIb-IIIa Inhibitor Integrelin During Coronary Angioplasty: Results of the IMPACT Study. Circulation 1993, 88, I-595, Abstract 3200.
35. Schulman, S. P.; Goldschmidt-Clermont, P. J.; Navetta, F. I.; Chandra, N. C.; Guerci, A. D.; Califf, R. M.; Ferguson, J. J.; Willerson, J. T.; Wolfe, C. L.; Bahr, R.; Yakubov, S. J.; Nygaard, T. W.; Mason, S. J.; Brashears, L.; Charo, I.; du Mée, C.; Kitt, M. M.; Gerstenblith, G. Integrelin in Unstable Angina: A Double Blind Randomized Trial. Circulation 1993, 88, I-608, Abstract 3272.
36. Barrett, J. S.; Murphy, G.; Peerlinck, K.; DeLepeleire, I.; Gould, R. J.; Panebianco, D.; Hand, E.; Deckmyn, H.; Vermylen, J.; Arnout, J. Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men. Clin. Pharmacol. Ther. 1994, 56, 377-388.
37. Théroux, P.; Kouz, S.; Knudtson, M. L.; Keils, C.; Nasmith, J.; Roy, L.; Dalle Ave, S.; Steiner, B.; Xiao, Z.; Rapold, H. J. A randomized double-blind controlled trial with the non-peptidic platelet GP IIb/IIIa antagonist Ro 44-9883 in unstable angina. Circulation 1994, 90, I-232, Abstract 1243.
38. Alig, L.; Edenhofer, A.; Hadváry, P.; Hürzeler, M.; Knopp, D.; Müller, M.; Steiner, B.; Trzeciak, A.; Weller, T. Low Molecular Weight, Non-Peptide Fibrinogen Receptor Antagonists. J. Med. Chem. 1992, 35, 4393-4407.
39. Cook, N. S.; Bruttger, O.; Pally, C.; Hagenbach, A. The Effects of Two Synthetic Glycoprotein IIb/IIIa Antagonists, Ro 43-8857 and L-700,462, on Platelet Aggregation and Bleeding in Guinea-Pigs and Dogs: Evidence that Ro 43-8857 Is Orally Active. Thromb. Haemostasis 1993, 70, 838-847.
40. Eldred, C. D.; Evans, B.; Hindley, S.; Judkins, B. D.; Kelly, H. A.; Kitchin, J.; Lumley, P.; Porter, B.; Ross, B. C.; Smith, K. J.; Taylor, N. R.; Wheatcroft, J. R. Orally Active Non-Peptide Fibrinogen Receptor (GpIIb/IIIa) Antagonists: Identification of 4-[4-[4-(Aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic Acid as a Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885.
41. Egbertson, M. S.; Naylor, A. M.; Hartman, G. D.; Cook, J. J.; Gould, R. J.; Holahan, M. A.; Lynch, J. J., Jr.; Lynch, R. J.; Stranieri, M. T.; Vassallo, L. M. Non-Peptide Fibrinogen Receptor Antagonists. 3. Design and Discovery of a Centrally Constrained Inhibitor. Bioorg. Med. Chem. Lett. 1994, 4, 1835-1840.
42. Barrett, J. S.; Gould, R. J.; Ellis, J. D.; Holahan, M. M.; Stranieri, M. T.; Lynch, J. J., Jr.; Hartman, G. D.; Ihle, N.; Duggan, M.; Moreno, O. A.; Theoharides, A. D. Pharmacokinetics and Pharmacodynamics of L-703,014, a Potent Fibrinogen Receptor Antagonist, After Intravenous and Oral Administration in the Dog. Pharm. Res. 1994, 11, 426-431.
43. Duggan, M. E.; Naylor-Olsen, A. M.; Perkins, J. J.; Anderson, P. S.; Chang, C. T.-C.; Cook, J. J.; Gould, R. J.; Ihle, N. C.; Hartman, G. D.; Lynch, J. J.; Lynch, R. J.; Manno, P. D.; Schaffer, L. W.; Smith, R. L. Non-Peptide Fibrinogen Receptor Antagonists. XX. Design and Synthesis of the Potent, Orally Active Fibrinogen Receptor Antagonist L-734,217. J. Med. Chem. 1995, 38, 3332-3341.
44. Müller, T. H.; Schurer, H.; Waldmann, L.; Bauer, E.; Himmelsbach, F.; Binder, K. Oral Activity of BIBU 104, a Prodrug of the Non-Peptide Fibrinogen Receptor Antagonist BIBU 52, in Mice and Monkeys. Thromb. Haemostasis 1993, 69, 975, Abstract 1557.
45. Bondinell, W. E.; Keenan, R. M.; Miller, W. H.; Ali, F. E.; Allen, A. C.; DeBrosse, C. W.; Eggleston, D. S.; Erhard, K. F.; Haltiwanger, R. C.; Huffman, W. F.; Hwang, S.-M.; Jakas, D. R.; Koster, P. F.; Ku, T. W.; Lee, C. P.; Nichols, A. J.; Ross, S. T.; Samanen, J. M.; Valocik, R. E.; Vasko-Moser, J. A.; Venslavsky, J. W.; Wong, A. S.; Yuan, C.-K. Design of a Potent and Orally Active Nonpeptide Platelet Fibrinogen Receptor (GP IIb/ IIIa) Antagonist. Bioorg. Med. Chem. 1994, 2, 897-908.
46. Bovy, P. R.; Tjoeng, F. S.; Rico, J. G.; Rogers, T. E.; Lindmark, R. J.; Zablocki, J. A.; Garland, R. B.; McMackins, D. E.; Dayringer, H.; Tóth, M. V.; Zupec, M. E.; Rao, S.; Panzer-Knodle, S. G.; Nicholson, N. S.; Salyers, A.; Taite, B. B.; Herin, M.; Miyano, M.; Feigen, L. P.; Adams, S. P. Design of Orally Active, Non-Peptide Fibrinogen Receptor Antagonists. An Evolutionary Process from the RGD Sequence to Novel Anti-Platelet Aggregation Agents. Bioorg. Med. Chem. 1994, 2, 881-895.
47. Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B. B.; Szalony, J. A.; Haas, M. F.; King, L. W.; Zablocki, J. A.; Keller, B. T.; Broschat, K.; Engleman, V. W.; Herin, M.; Jacqmin, P.; Feigen, L. P. SC-54684A: An Orally Active Inhibitor of Platelet Aggregation. Circulation 1995, 91, 403-410.
48. Szalony, J. A.; Haas, M. F.; Salyers, A. K.; Taite, B. B.; Nicholson, N. S.; Mehrotra, D. V.; Feigen, L. P. Extended Inhibition of Platelet Aggregation With the Orally Active Platelet Inhibitor SC-54684A. Circulation 1995, 91, 411-416.
49. Anders, R. J.; Alexander, J. C.; Hantsbarger, G. L.; Burns, D. M.; Oliver, S. D.; Cole, G.; Fitzgerald, D. J. Demonstration of Potent Inhibition of Platelet Aggregation with an Orally Active GP IIb/IIIa Receptor Antagonist. J. Am. Coll. Cardiol. (Suppl.) 1995, 117A.
50. Zablocki, J. A.; Rico, J. G.; Garland, R. B.; Rogers, T. E.; Williams, K.; Schretzman, L. A.; Rao, S. A.; Bovy, P. R.; Tjoeng, F. S.; Lindmark, R. J.; Tóth, M. V.; Zupec, M. E.; McMackins, D. E.; Adams, S. P.; Miyano, M.; Markos, C. S.; Milton, M. N.; Paulson, S.; Herin, M.; Jacqmin, P.; Nicholson, N. S.; Panzer-Knodle, S. G.; Haas, N. F.; Page, J. D.; Szalony, J. A.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. (Aminobenzamidino)succinyl (ABAS) Series of Orally Active Fibrinogen Receptor Antagonists. J. Med. Chem. 1995, 38, 2378-2394.
51. Zablocki, J. A.; Tjoeng, F. S.; Bovy, P. R.; Miyano, M.; Garland, R. B.; Williams, K.; Schretzman, L.; Zupec, M. E.; Rico, J. G.; Lindmark, R. J.; Tóth, M. V.; McMackins, D. E.; Adams, S. P.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. A Novel Series of Orally Active Antiplatelet Agents. Bioorg. Med. Chem. 1995, 3, 539-551.
52. Hamprecht, G. Ger. Offen. DE 3,134,144, March 17, 1983.
53. Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Müller, T.; Weisenberger, J.; Linz, G.; Krüger, G. Eur. Pat. Appl. 483 667, May 6, 1992.
54. Korbonits, D.; Kiss, P.; Simon, K.; Kolonits, P. Synthese von 4-Aminopyrimidinen aus 1,2,4-Oxadiazolen, I. (Synthesis of 4-aminopyrimidines from 1,2,4-oxadiazoles. I. New general method for the preparation of 4-aminoquinazolines and their hetero analogs.) Chem. Ber. 1984, 117, 3183-3193.
55. Walters, L. R.; Siegel, M. I.; Cook, R. C. Reaction of Hydroxylamine with a Reissert Compound. J. Heterocycl. Chem. 1968, 5, 577-578.
56. Jendralla, H.; Seuring, B.; Herchen, J.; Kulitzscher, B.; Wunner, J.; Stüber, W.; Koschinsky, R. Efficient Kg-Scale Synthesis of Thrombin Inhibitor CRC 220. Tetrahedron 1995, 51, 12047-12068.
57. 2. Polyhedron 1989, 8, 301-304.
58. Fujimoto, K.; Ishihara, S.; Yanagisawa, H.; Ide, J.; Nakayama, E.; Nakao, H.; Sugawara, S.; Iwata, M. Studies on Orally Active Cephalosporin Esters. J. Antibiot. 1987, 40, 370-384.
59. Hauptmann, J.; Paintz, M.; Kaiser, B.; Richter, M. Reduction of a benzamidoxime derivative to the corresponding benzamidine in vivo and in vitro. Pharmazie 1988, 43, 559-560.
60. Clement, B.; Zimmermann, M.; Schmitt, S. Biotransformation des Benzamidins und des Benzamidoxims durch mikrosomale Enzyme vom Kaninchen. (Biotransformation of benzamidine and benzamidoxime by microsomal enzymes of the rabbit.) Arch. Pharm. (Weinheim, Ger.) 1989, 322, 431-435.
61. Clement, B.; Immel, M.; Terlinden, R.; Wingen, F.-J. Reduction of Amidoxime Derivatives to Pentamidine in vivo. Arch. Pharm. (Weinheim, Ger.) 1992, 325, 61-62.
62. Clement, B.; Jung, F. N-Hydroxylation of the antiprotozoal drug pentamidine catalyzed by rabbit liver cytochrome P-450 2C3 or human liver microsomes, microsomal retroreduction, and further oxidative transformation of the formed amidoximes. Drug Metab. Dispos. 1994, 22, 486-497.
63. Pearse, J., G. A.; Pflaum, R. T. Interaction of Metal Ions with Amidoxims. J. Am. Chem. Soc. 1959, 81, 6505-6508.
64. Sheldrick, G. M. SHELXL-93 Program for Crystal Structure Refinement, University of Göttingen: Germany, 1993.
65. Tanswell, P.; Koup, J. TopFit: A PC-based pharmacokinetics/ pharmacodynamics data analysis program. Int. J. Clin. Pharmacol. Toxicol. 1993, 31, 514-520.