Structure-based design of potent, amidine-derived inhibitors of factor Xa: Evaluation of selectivity, anticoagulant activity, and antithrombotic activity

Journal of Medicinal Chemistry

Volumn 43, Issue 5, 2000, Pages 883-899

  Wiley, Michael R ^a   Weir, Leonard C ^a   Briggs, Steven ^a   Bryan, Nancy A ^a   Buben, John ^a   Campbell, Charles ^a   Chirgadze, Nickolay Y ^a   Conrad, Richard C ^a   Craft, Trelia J ^a   Ficorilli, James V ^a   Franciskovich, Jeffry B ^a   Froelich, Larry L ^a   Gifford Moore, Donetta S ^a   Goodson Jr , Theodore ^a   Herron, David K ^a   Klimkowski, Valentine J ^a   Kurz, Kenneth D ^a   Kyle, Jeffery A ^a   Masters, John J ^a   Ratz, Andrew M ^a   Milot, Guy ^a   Shuman, Robert T ^a   Smith, Tommy ^a   Smith, Gerald F ^a   Tebbe, Ann Louise ^a   Tinsley, Jennifer M ^a   Towner, Richard D ^a   Wilson, Alexander ^a   Yee, Ying K ^a   more..

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING FACTOR 10A INHIBITOR; THROMBIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTICOAGULATION; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; ENZYME ACTIVE SITE; MALE; MOLECULAR MODEL; NONHUMAN; RABBIT; RAT; STRUCTURE ACTIVITY RELATION; THROMBOSIS;

AMIDINES; ANIMALS; ANTICOAGULANTS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DOGS; DRUG DESIGN; ENZYME INHIBITORS; FACTOR XA; FIBRINOLYTIC AGENTS; HUMANS; MALE; MODELS, MOLECULAR; PROTHROMBIN TIME; RABBITS; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBIN; THROMBOSIS;

EID: 0034624689     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9903287     Document Type: Article

References (59)

1. (a) Vacca, J. P. Thrombosis and coagulation. Annu. Rep. Med. Chem. 1998, 33, 81-90.
2. (b) Ripka, W. C.; Vlasuk, G. P. Antithrombotics -serine proteases. Annu. Rep. Med. Chem. 1997, 32, 71-89.
3. (a) Meade, W. M.; Miller, G. J.; Rosenberg. Characteristics Associated with the Risk of Arterial Thrombosis. In Cardiovascular Thrombosis: Thrombocardiology and Thromboneurology, 2nd ed.; Verstraete, M., Fuster, V., Topol, E. J., Eds.; Lippincott-Raven Publishers: Philadelphia, 1998; pp 77-89.
4. (b) Carter, C. J.; Sammama, M. M. Characteristics Associated with the Risk of Venous Thrombosis. In Cardiovascular Thrombosis: Thrombocardiology and Thromboneurology, 2nd ed.; Verstraete, M., Fuster, V., Topol, E. J., Eds.; Lippincott-Raven Publishers: Philadelphia, 1998; pp 91-102.
5. (a) Amerena, J.; Mashford, M. L.; Wallace, S. Adverse effects of anticoagulants. Adverse Drug React. Acute Poisoning Rev. 1990, 9, 1-36.
6. (b) Levine, M. N.; Hirsh, J.; Salzman, E. W. Side effects of antithrombotic therapy. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice; Colman, R. W., Hirsh, J., Marder, V. J., Salzman, E. W., Eds.; J. B. Lippincott Co.: Philadelphia, 1994; pp 936-955.
7. (c) Williams, E. C.; Suttie, J. W. Vitamin K antagonists. In Cardiovascular Thrombosis: Thrombocardiology and Thromboneurology; Verstraete, M., Fuster, V., Topol, E. J., Eds.; Lippincott-Raven: Philadelphia, 1998; pp 285-300.
8. (d) Hirsh, J. Oral Anticoagulants. N. Engl. J. Med. 1991, 324, 1865-1875.
9. Wiley, M. R.; Fisher, M. J. Small-molecule direct thrombin inhibitors. Exp. Opin. Ther. Patents 1997, 7 (11), 1265-1282.
10. Lawson, J. H.; Kalafatis, M.; Stram, S.; Mann, K. G. A model for the tissue factor pathway to thrombin. J. Biol. Chem. 1994, 269 (37), 23357-23366.
11. Vlasuk, G. P. Structural and Functional Characterization of Tick Anticoagulant Peptide (TAP): A Potent and Selective Inhibitor of Blood Coagulation Factor Xa. Thromb. Haemostasis 1993, 70 (1), 212-216.
12. Schaffer, L. W.; Davidson, J. T.; Vlasuk, G. P.; Dunwiddie, C. T.; Siegl, P. K. S. Selective Factor Xa Inhibition by Recombinant Antistasin Prevents Vascular Graft Thrombosis in Baboons. Arterioscl. Thromb. 1992, 12, 879-885.
13. Wong, A. G.; Gunn, A. C.; Ku, P.; Hollenbach, S. J.; Sinha, U. Relative Efficacy of Active Site-Blocked Factors IXa, Xa in Models of Rabbit Venous and Arterio-Venous Thrombosis. Thromb. Haemostasis 1997, 77, 1143-1147.
14. G. F. Smith, Lilly Research Laboratories, unpublished results.
15. Herron, D. K.; Goodson, T., Jr.; Wiley, M. R.; Weir, L. C.; Kyle, J. A.; Yee, Y. K.; Tebbe, A. L.; Tinsley, J. M.; Mendel, D.; Masters, J. J.; Franciskovich, J. B.; Sawyer, J. S.; Beight, D. W.; Ratz, A. M.; Milot, G.; Hall, S. E.; Klimkowski, V. J.; Wikel, J. H.; Eastwood, B. J.; Towner, R. D.; Gifford-Moore, D.; Craft, T. J.; Smith, G. F. 1,2-Dibenzamidobenzene Inhibitors of Human Factor Xa. J. Med. Chem. 2000, 43, 859-872.
16. (a) Wiley, M. R.; Chirgadze, N. Y.; Clawson, D. K.; Craft, T. J.; Gifford-Moore, D. S.; Jones, N. D.; Olkowski, J. L.; Weir, L. C.; Smith, G. F. D-Phe-Pro-p-amidinobenzylamine: a potent and highly selective thrombin inhibitor. Bioorg. Med. Chem. Lett. 1996, 6 (20), 2387-2392.
17. (b) Sturzebecher, J.; Markwardt, F.; Viogt, B.; Wagner, G.; Walsmann, P. Cyclic amides of N-α-arylsulfonylamino-acylated-4-amidinophenylalanine: tight binding inhibitors of thrombin. Thromb. Res. 1983, 29, 635-642.
18. (a) Nagahara, T.; Yokoyama, Y.; Inamura, K.; Katakura, S.; Komoriya, S.; Yamaguchi, H.; Hara, T.; Iwamoto M. Dibasic (amidinoaryl)propanoic acid derivatives as novel blood coagulation factor Xa inhibitors. J. Med. Chem. 1994, 37, 1200-1207.
19. (b) Quan, M. L.; Pruitt, J. R.; Ellis, C. D.; Liaw, A. Y.; Galemmo, R. A. Jr.; Stouten, P. F. W.; Wityak, J.; Knabb, R. M.; Thoolen, M. J.; Wong, P. C.; Wexler, R. R. Bisbenzamidine isoxazoline derivatives as factor Xa inhibitors. Bioorg. Med. Chem. Lett. 1997, 7, 2813-2818.
20. (c) Shaw, K. J.; Guilford, W. J.; Dallas, J. L.; Koovakkaat, S. K.; McCarrick, M. A.; Liang, A.; Light, D. R.; Morrissey, M. M. (Z,Z)-2,7-Bis(4-amidinobenzylidene) cycloheptan-1-one: Identification of a Highly Active Inhibitor of Blood Coagulation Factor Xa. J. Med. Chem. 1998, 41, 3551.
21. (d) Philips, G. B.; Buckman, B. O.; Davey, D. D.; Eagen, K. A.; Guilford, W. J.; Hinchman, J.; Ho, E.; Koovakkat, S.; Liang, A.; Light, D. R.; Mohan, R.; Ng, H. P.; Post, J. M.; Shaw, K. J.; Smith, D.; Subramanyam, B.; Sullivan, M. E.; Trinh, L.; Vergona, R.; Walters, J.; White, K.; Whitlow, M.; Wu, S.; Xu, W.; Morrisey, M. M. Discovery of N-[2-[5-[Amino(imino)methyl]-2-hydroxyphenoxy]-3,5-difluoro-6-[3-(4,5-dihydro-1- methyl-1H-imidazol-2-yl)phenoxy]pvridm-4-yl]-N-methylglycine (ZK-807834): A Potent, Selective and Orally Active Inhibitor of the Blood Coagulation Enzyme Factor Xa. J. Med. Chem. 1998, 41, 3557.
22. (e) Gabriel, B.; Stubbs, M. T.; Bergner, A.; Hauptmann, J.; Bode, W.; Sturzebecher, J.; Maroder, L. Design of benzamidine-type inhibitors of factor Xa. J. Med. Chem. 1998, 41, 4240-4250.
23. (f) Kucznierz, R.; Grams, F.; Leinert, H.; Marzenell, K.; Engh, R. A.; von der Saal, W. Tetrahydroisoquinoline-based factor Xa inhibitors. J. Med. Chem. 1998, 41, 4983-4994.
24. (g) Galemmo, R. A., Jr.; Maduskie, T. P.; Dominguez, C.; Rossi, K. A.; Knabb, R. M.; Wexler, R. R.; Stouten, P. F. W. The de novo design and synthesis of cyclic urea inhibitors of factor Xa: initial SAR studies. Bioorg. Med. Chem. Lett. 1998, 8, 2705-2710.
25. (h) Buckman, B. O.; Mohan, R.; Koovakkat, S.; Liang, A.; Trinh, L.; Morrissey, M. M. Design, synthesis and biological activity of novel purine and bicyclic pyrimidine factor Xa inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 2235.
26. Padmanabhan, K.; Padmanabhan, K. P.; Tulinsky, A.; Park C. H.; Bode, W.; Huber, R.; Blankenship, D. T.; Cardin, A. D.; Kisiel W. Structure of human des(1-45) Factor Xa at 2.2 Å resolution. J. Mol. Biol. 1993, 232, 947-966.
27. 2-Aroylanthranilamide Inhibitors of Human Factor Xa. J. Med. Chem. 2000, 43, 873-882.
28. Fisher, M. J.; Gunn, B.; Harms C. S.; Kline, A. D.; Mullaney, J. T.; Nunes A.; Scarborough, R. M.; Arfsten, A. E.; Skelton, M. A.; Um S. L.; Utterback, B. G.; Jakubowski, J. A. Non-peptide RDG surrogates which mimic a Gly-Asp β-turn: potent antagonists of platelet glycoprotein IIbIIIa. J. Med. Chem. 1997, 40, 2085-2101.
29. Judkins, B. D.; Allan, D. G.; Cook, T. A.; Evans, B.; Sardharvala, T. E. Synth. Commun. 1996, 26 (23), 4351-4367.
30. (a) Baker, E. N.; Hubbard, R. E. Hydrogen bonding in globular proteins. Prog. Biophys. Mol. Biol. 1984, 44, 97-197.
31. (b) McDonald, I. K.; Thornton, J. M. Satisfying hydrogen bonding potential in proteins. J. Mol. Biol. 1994, 238, 777-793.
32. Bode, W.; Turk, D.; Karshikov, A. The refined 1.9 X-ray crystal structure of D-Phe-Pro-Arg chloromethyl ketone-inhibited human α-thrombin. Structure analysis, overall structure, electrostatic properties, detailed active-site geometry, structure -function relationships. Protein Sci. 1992, 1, 426-471.
33. (a) Chow, M. M.; Meyer, E. F., Jr.; Bode, W.; Kam, C.-M.; Radhakrishnan, R.; Vijayalakshmi, J.; Powers, J. C. The 2.2A resolution X-ray crystal structure of the complex of trypsin inhibited by 4-chloro-3-ethoxy-7-guanidinocoumarin: A proposed model of the thrombin-inhibitor complex. J. Am. Chem. Soc. 1990, 112, 7783-7789.
34. (b) Bode, W.; Truk, D.; Sturzebecher, J. Geometry of binding of the benzamidine-and arginine-based inhibitors NAPAP and MQPA to human a-thrombin. X-ray crystallographic determination of the NAPAP-trypsin complex and modeling of NAPAP-thrombin and MQPA-thrombin. Eur. J. Biochem. 1990, 193, 175-182.
35. Renatus, M.; Bode, W.; Huber, R.; Sturzebecher, 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.
36. Chirgadze, N. Y.; Sall, D. J.; Hermann, R.; Clawson D. K.; Klimkowski, V. J.; Smith G. F.; Gifford-Moore D. S.; Coffman, W. J. The crystal structure of human α-thrombin complexed with LY178550, a nonpeptidyl, active-site directed inhibitor. Protein Sci. 1997, 6 (7), 1412-1417.
37. (a) Wiley, M. R.; Chirgadze, N. Y.; Clawson, D. K.; Craft, T. J.; Gifford-Moore, D. S.; Jones, N. D.; Olkowski, J. L.; Schacht, A. L.; Weir, L. C.; Smith, G. F. The serine protease selectivity of the thrombin inhibitor D-Phe-Pro-Agmatine and its homologues. Bioorg. Med. Chem. Lett. 1995, 5 (3), 2835-2840.
38. (b) Smith, G. F.; Shuman, R. T.; Craft, T. J.; Gifford-Moore D. S.; Kurz, K. D.; Jones, N. D.; Chirgadze, N.; Hermann, R. B.; Coffman, W. J.; Sandusky, G. E.; Roberts, E.; Jackson. C. V. A family of arginal thrombin inhibitors related to efegatran. Sem. Thromb. Hemostasis 1996, 22 (2), 173-183.
39. Katakura, S.; Nagahara, T.; Hara, T.; Iwamoto, M. A novel factor Xa inhibitor: structure-activity and selectivity between factor Xa and thrombin. Biochem. Biophys. Res. Commun. 1995, 30, 387-394.
40. (a) Shuman, R. T.; Rothenberger, R. B.; Jackson, C. V.; Roberts, E. W.; Singer, B.; Lucas, R. A.; Kurz, K. D. Oral activity of tripeptide aldehyde thrombin inhibitors. In Peptides: Chemistry, Structure and Biology; Pravin, Kaumaya, T. P., Hodges, R. S., Eds.; Mayflower Scientific Ltd., 1996; p 215.
41. (b) Shuman, R. T.; Rothenberger, R. B.; Campbell, C. S.; Smith G. F.; Gifford-Moore D. S.; Paschal, J. W.; Geselchen, P. D. Structure activity study of tripeptide thrombin inhibitor using α-alkyl amino acids and other conformationally constrained amino acid substitutions. J. Med. Chem. 1995, 38, 4446-4453.
42. The species selectivity profile reported here is similar to that reported for DX-9065a. In the DX-9065a study, fXa from other species was isolated and evaluated to demonstrate that differences in enzyme affinity were responsible for the differences in anticoagulant activity. Hara, T.; Kunitada, S.; Iwamato, M. DX-9065a, a synthetic and selective factor Xa inhibitor: species difference in its anitcoagulant activity. Thromb. Haemostasis 1993, 69, 890 (Suppl.).
43. (a) Smith, J. R.; White, A. M. Fibrin, red cell and platelet interactions in an experimental model of thrombosis. Br. J. Pharmaco.l 1982, 77, 29-38.
44. (b) Ashida, S.; Sakuma, K.; Abido, Y. Antithrombotic effects of ticlopidine, acetylsalicylic acid and dipyridamole in vascular shunt model in rats. Thromb. Res. 1980, 17, 663-671.
45. Molecular Simulations Inc., 9685 Scranton Rd., San Diego, CA 92121.
46. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J.; Swaminathan, S.; Karplus, M. CHARMM: A Program for Macromolecular Energy, Minimization, and Dynamics Calculations. J. Comput. Chem. 1983, 4, 187-217.
47. Hermann, R. B.; Herron, D. K. OVID and SUPER: Two overlap programs for drug design. J. Comput.-Aided Mol. Des. 1991, 5, 511-524.
48. Sall, D. J.; Bastian J. A.; Briggs, S. L.; Buben J. A.; Clawson, D. K.; Denney, M. L.; Giera D. D.; Gifford-Moore, D. S.; Harper, R. W.; Hauser K. L.; Klimkowski, V. J.; Kohn, T. J.; Lin, H.-S.; McCowan, J. R.; Palkowitz, A. D.; Smith G. F.; Takeuchi K.; Thrasher K. J.; Tinsley J. M.; Utterback, B. G.; Yan, S.-C. B.; Zhang, M. Dibasic benzo[6]thiophene derivatives as a novel class of active site-directed thrombin inhibitors. 1. Determination of the serine protease selectivity, structure-activity relationships, and binding orientation. J. Med. Chem. 1997, 40 (22), 3489-3493.
49. (a) Smith, G. F.; Gifford-Moore, D. S.; Craft, T. J.; Chirgadze, N.; Ruterbories, K. J.; Lindstrom, T. D.; Satterwhite, J. H. Efegatran: A New Cardiovascular Anticoagulant. In New Anticoagulants for the Cardiovascular Patient; Pifarre, R., Ed.; Hanley & Belfus, Inc.: Philadelphia, 1997; pp 265-300.
50. (b) Sall, D. J.; Bastian, J. A.; Chirgadze, N. Y.; Denny, M. L.; Fisher, M. J.; Gifford-Moore, D. S.; Harper, R. W.; Klimkowski, V. J.; Kohn, T. J.; Lin, H. S.; McCowan, J. R.; Richett, M. E.; Smith, G. F.; Takeuchi, K.; Toth, J. E.; Zhang, M. Diaminobenzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 5. Potency, efficacy and pharmacokinetic properties of modified C-3 side chain derivatives. J. Med. Chem. 2000, 43, 649-663.
51. (a) Sall, D. J.; Briggs, S. L.; Clawson, D. K.; Gifford-Moore, D. S.; Klimkowski, V. J.; McCowan, J. R.; Smith, G. F.; Wikel, J. H. Dibasic benzo[b]thiophenes derivatives as a novel class of active site directed thrombin inhibitors. 2. exploring interactions at the proximal (S2) binding site. Bioorg. Med. Chem. Lett. 1998, 8, 2527-2532.
52. (b) Chirgadze, N. Y.; Sall, D. J.; Briggs, S. L.; Clawson, D. K.; Zhang, M.; Smith, G. F.; Schevitz, R. W. The crystal structures of human α-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a novel binding mode for a structurally unique class of inhibitors. Protein Sci. 1999, in press.
53. (c) Schacht, A. L.; Chirgadze, N.; Clawson, D.; Craft, T. J.; Coffman, W. J.; Jones, N. D.; Gifford-Moore, D. S.; Olkowski, J.; Shuman, R. T.; Smith, G. F.; Weir, L. C.; Wiley, M. R. N-Substituted glycines as replacements for proline in tripeptide aldehyde thrombin inhibitors. Bioorg. Med. Chem. Lett. 1995, 5, 2529-2534.
54. (d) Johnson, M. G.; Bronson, D. D.; Gillispie, J. E.; Gifford-Moore, D. S.; Kalter, K.; Lynch, M. P.; McGowan, J. R.; Redick, C. C.; Sall, D. J.; Smith, G. F.; Fogelsong, R. J. Solid-phase chemistry approach to the SAR development of a novel class of active site-directed thrombin inhibitors. Tetrahedron 1999, 55, 11641-11652.
55. (e) Bastian, J. A.; Sall, D. J.; Chirgadze, N. Y.; Denny, M. L.; Gifford-Moore, D. S.; Smith, G. F.; Wikel, J. H. Diamino benzo[b]thiophenes derivatives as a novel class of active site directed thrombin inhibitors. 3. Enhancing activity by imposing conformational restriction in the C-4 side chain. Bioorg. Med. Chem. Lett. 1999, 8, 363-368.
56. (f) Takeuchi, K.; Kohn, T. J.; Sall, D. J.; Denny, M. L.; McGowan, J. R.; Smith, G. F.; Gifford-Moore D. S. Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes. Bioorg. Med. Chem. Lett. 1999, 9, 759-764.
57. (g) Wiley, M. R.; Weir, L. C.; Briggs, S. L.; Chirgadze, N. Y.; Clawson, D.; Gifford-Moore, D. S.; Schacht, A. L.; Smith, G. F.; Vasudevan, V.; Zornes, L. L.; Klimkowski, V. J. The design of potent, selective, non-covalent, peptide thrombin inhibitors utilizing imidazole as a S1 binding element. Bioorg. Chem. Med. Lett. 1999, 9, 2767-2772.
58. (a) Henderson, P. J. F. A linear equation that describes the steady-state kinetics of enzymes and subcellular particles interacting with tightly bound inhibitors. Biochem. J. 1972, 127, 321-333.
59. (b) Bieth, J. G. Pathophysiological interpretation of kinetic constants of protease inhibitors. Bull. Eur. Physiopath. Resp. 1980, 16 (Suppl.), 183-195.