Fused bicyclic Gly-Asp β-turn mimics with specific affinity for GPIIb- IIIa

Journal of Medicinal Chemistry

Volumn 42, Issue 23, 1999, Pages 4875-4889

  Fisher, Matthew J ^a   Arfstan, Ann E ^c   Giese, Ulrich ^b   Gunn, Bruce P ^a   Harms, Cathy S ^a   Khau, Vien ^a   Kinnick, Michael D ^a   Lindstrom, Terry D ^a   Martinelli, Michael J ^a   Mest, Hans Jürgen ^b   Mohr, Michael ^b   Morin Jr , John M ^a   Mullaney, Jeffrey T ^a   Nunes, Anne ^a   Paal, Michael ^b   Rapp, Achim ^b   Rühter, Gerd ^b   Ruterbories, Ken J ^a   Sall, Daniel J ^a   Scarborough, Robert M ^c   Schotten, Theo ^b   Sommer, Birgit ^b   Stenzel, Wolfgang ^b   Towner, Richard D ^a   Um, Suzane L ^a   Utterback, Barbara G ^a   Vasileff, Robert T ^a   Vöelkers, Silke ^b   Wyss, Virginia L ^a   Jakubowski, Joseph A ^a   more..

^a ELI LILLY AND COMPANY   (United States)

^b Lilly Research Laboratories   (Germany)

^c MILLENNIUM PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 TETRALONE DERIVATIVE; BENZOPYRAN DERIVATIVE; FIBRINOGEN RECEPTOR; FIBRINOGEN RECEPTOR ANTAGONIST; ISOQUINOLINE DERIVATIVE; TETRALIN DERIVATIVE;

ANIMAL EXPERIMENT; ARTICLE; CYCLIZATION; DRUG BIOAVAILABILITY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; NONHUMAN; RAT; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BENZOPYRANS; BINDING, COMPETITIVE; BIOLOGICAL AVAILABILITY; ENZYME-LINKED IMMUNOSORBENT ASSAY; GUINEA PIGS; HUMANS; ISOQUINOLINES; MOLECULAR MIMICRY; OLIGOPEPTIDES; PLATELET AGGREGATION; PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX; PROTEIN STRUCTURE, SECONDARY; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAHYDRONAPHTHALENES;

EID: 0032751692     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990365y     Document Type: Article

References (59)

1. For recent reviews, see: (a) Samanen, J. Annu. Rep. Med. Chem. 1996, 1, 91-100.
2. (b) Ogima, I.; Chakravarty, S.; Dong, Q. Antithrombotic Agents: From RGD to Peptide Mimetics. Bioorg. Med. Chem. 1995, 3, 337-360.
3. Colman, R. W.; Marder, V. J.; Salzman, E. W.; Hirsch, J. Overview of hemostasis. Hemostasis Thrombosis 1993, 3-18.
4. Phillips, D. R.; Fitzgerald, L. A.; Charo, I. F.; Parise, L. V. The Platelet Glycoprotein IIb/IIIa Complex. Ann. N. Y. Acad. Sci. 1987, 509, 177-187.
5. Phillips, D. R.; Charo, I. F.; Parise, L. V.; Fitzgerald, L. A. The Platelet Membrane Glycoprotein IIb/IIIa Complex. Blood 1988, 71, 831-843.
6. Phillips, D. R.; Charo, I. F.; Scarborough, R. M. GPIIb-IIIa: The Responsive Integrin. Cell 1991, 65, 359-362.
7. Pytela, R.; Pierschbacher, M. D.; Ginsberg, M. H.; Plow, E. F.; Rouslahti, E. Platelet Membrane Glycoprotein IIb/IIIa: Member of a Family of Arg-Gly-Asp-Specific Adhesion Receptors. Science 1986, 237, 1559-1562.
8. Hawiger, J.; Kloczewiak, M.; Bednarek, M. A.; Timmons, S. Platelet Receptor Recognition Domains on the a Chain of Human Fibrinogen: Structure-Function Analysis. Biochemisry 1989, 28, 2909-2914.
9. Bennett, J. S.; Shattil, S. J.; Power, S. W.; Gartner, T. K. Interaction of Fibrinogen with Its Platelet Receptor. J. Biol. Chem. 1988, 263, 12948-12953.
10. 2+ dependent Binding of a Synthetic Arg-Gly-Asp (RGD) Peptide to a Single Site on the Purified Platelet Glycoprotein IIb-IIIa complex. J. Biol. Chem. 1989, 264, 13102-13108.
11. For a review and leading references, see: (a) Nichols, A. J.; Ruffolo, R. R., Jr.; Huffman, W. F.; Proste, G.; Samanen, J. Trends Pharmacol. Sci. 1992, 13, 413.
12. (b) Shebuski, R. J. Annu. Rep. Med. Chem. 1991, 26, 93.
13. Samanen, J.; Ali, F. E.; Romoff, T.; Calvo, R.; Sorenson, E.; Bennett, D.; Berry, D.; Koster, P.; Vasko, J.; Powers, D.; Stadel, J.; Nichols, A. Reinstatement of High Receptor Affinity in a Peptide Fragment (RGDS) Through Conformational Constraints. In Peptides 1990, Proceedings of the 21st European Peptide Symposium; Giralt, E., Andreu, D., Eds.; ESCOM Science Publishers: Leiden, 1990; pp 781-783.
14. Samanen, J.; Ali, F.; Romoff, T.; Calvo, R.; Sorenson, E.; Vasko, J.; Storer, B.; Berry, D.; Bennett, D.; Stroksacker, M.; Powers, D.; Stadel, J.; Nichols, A. Development of a Small RGD Peptide Fibrinogen Receptor Antagonist with Potent Antiaggregatory Activity in Vitro. J. Med. Chem. 1991, 34, 3114-3125.
15. Nutt, R. F.; Brady, S. F.; Sisko, J. T.; Ciccarone, T. M.; Colton, C. D.; Levy, M. R.; Gould, R. J.; Shang, G.; Friedman, P. A.; Veber, D. F. Structure and Conformation-Activity Studies Leading to Potent Fibrinogen Receptor Antagonists Containing Arg-Gly-Asp. In Peptides 1990; Giralt, E., Andreu, D., Eds.; ESCOM Science Publishers B.V.: Leiden, 1991; pp 784-784.
16. Ali, F. E.; Samanen, J. M.; Calvo, R.; Romoff, T.; Yellin, T.; Vasko, J.; Powers, D.; Stadel, J.; Bennett, D.; Berry, D.; Nichols, A. Potent Fibrinogen Receptor Antagonists Bearing Conformational Constraints. In Peptides, Chemistry and Biology, Proceedings of the 12th American Peptide Symposium; Smith, J. A., Rivier, J. E., Eds.; ESCOM: Leiden, 1992; pp 761-762.
17. Nutt, R. F.; Brady, S. F.; Colton, C. D.; Sisko, J. T.; Ciccarone, T.; Levey, M. R.; Duggan, M. E.; Imagire, I. S.; Gould, R. J.; Anderson, P. S.; Veber, D. F. Development of Novel, Highly Selective Fibrinogen Receptor Antagonists as Potentially Useful Antithrombotic Agents. In Peptides: Chemistry and Biology, Proceedings of the 12th American Peptide Symposium; Smith, J. A., River, J. E., Eds.; ESCOM: Leiden, 1992; pp 914-916.
18. Barker, P. L.; Bullens, S.; Bunting, S.; Burdick, D. J.; Chan, K. S.; Deisher, T.; Eigenbrot, C.; Gadek, T. R.; Gantzos, R.; Lipari, M, T.; Muir, C. D.; Napier, M. A.; Pitti, R. M.; Padua, A.; Quan, C.; Stanley, M.; Struble, M.; Tom, J. Y. K.; Burnier, J. P. Cyclic RGD Analogues as Antiplatelet Antithrombotics. J. Med. Chem. 1992, 35, 2040-2048.
19. Ali, F. E.; Bennett, D. B.; Raul, C. R.; Elliott, J. D.; Hwand, S.-M.; Ku, T. W.; Lago, M. A.; Nichols, A. J.; Romoff, T. T.; Shah, D. H.; Vasko, J. A.; Wong, A. S.; Yellin, T. O.; Yuan, C.-K.; Samanen, J. M. Conformationally Constrained Peptides and Semipeptides Derived from RGD as Potent Inhibitors of the Platelet Fibrinogen Receptor and Platelet Aggregation. J. Med. Chem. 1994, 37, 769-780
20. 3 Antagonists. J. Med. Chem. 1994, 37, 1-8.
21. Jackson, S.; DeGrado, W.; Dwivedi, A.; Parthasarathy, A.; Higley, A.; Krywko, J.; Rockwell, A.; Markwalder, J.; Wells, G.; Wexler, R.; Mousa, S.; Harlow, R. Template-Constrained Cyclic Peptides: Design of High-Affinity Ligands for GPIIb/IIIa. J. Am. Chem. Soc. 1994, 116, 3220-3230.
22. Hartman, G. D.; Egbertson, M. S.; Halczenko, W.; Laswell, W. L.; Duggan, M. E.; Smith, R. L.; Naylor, A. M.; Manno, P. D.; Lynch, R. J.; Zhang, G.; Cheng, C. T.-C.; Gould, R. J. Non-Peptide Fibrinogen Receptor Antagonists. 1. Discovery and Design of Exosite Inhibitors. J. Med. Chem. 1992, 35, 4640-4642.
23. Egbertson, M. S.; Chang, C. T.-C.; Duggan, M. E.; Gould, R. J.; Halczenko, W.; Hartman, G. D.; Laswell, W. L.; Lynch, J. J.; 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. J. Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-Asp. J. Med. Chem. 1994, 34, 2537-2551.
24. 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. 7. Design and Synthesis of a Potent, Orally Active Fibrinogen Receptor Antagonist. J. Med. Chem. 1995, 38, 3332-3341.
25. Klein, S. I.; Molino, B. F.; Czekaj, M.; Dener, J. S.; Leadley, R. J.; Sabatino, R.; Dunwiddie, C. T.; Chu, V. Non-Peptide Fibrinogen Receptor Antagonist Based Upon a 4-Substituted Piperidine Scaffold. Bioorg. Med. Chem. Lett. 1996, 6, 1403-1408.
26. Alig, L.; Edenhofer, A.; Hadvary, P.; Hurzeler, M.; Knopp, D.; Muller, T.; Steiner, B.; Trzeciak, A.; Weller, T. Low Molecular Weight, Non-Peptide Fibrinogen Receptor Antagonists. J. Med. Chem. 1992, 35, 4393-4407.
27. Stilz, H. U.; Jablonka, B.; Just, M.; Knolle, J.; Paulus, E. F.; Zoller, G. Discovery of an Orally Active Non-Peptide Fibrinogen Receptor Antagonist. J. Med. Chem. 1996, 39, 2118-2122.
28. Eldred, C. P.; Evans, B.; Hindley, S.; Judkins, B. D.; Kelly, H. A.; Kitchin, J.; Lumley, B. D.; 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-(Aminoimino-methyl)Phenyl]-1-Piperazinyl-1-Piperidineacetic acid as a Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885.
29. Zablocki, J. A.; Miyano, M.; Garland, R. B.; Pireh, D.; Schretzman, L.; Rao, S. N.; Lindmark,.J.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Champion, J. B.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp-Phe Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interaction Between the Arg Guanidine of RGDX mimetics and the Platelet GPIIb-IIIa receptor. J. Med. Chem. 1993, 36, 1811-1819.
30. Zablocki, J. A.; Miyano, M.; Rao, S. N.; Panzer-Knodle, S.; Nicholson, N.; Feigen, L. Potent Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp-Phe Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interaction Between the Asp Carboxylate of RGDX mimetics and the Platelet GPIIb-IIIa receptor. J. Med. Chem. 1992, 35, 4914-4917.
31. Ku, T. W.; Ali, F. E. Barton, L. S.; Bean, J. W.; Bondinell, W. E.; Burgess, J. L.; Callahan, J. F.; Calvo, R. R.; Chen, L.; Eggelston, D. S.; Gleason, J. G.; Huffman, W. F.; Hwang, S. M.; Jakas, D. R.; Karash, C. B.; Keenan, R. M.; Kopple, K. D.; Miller, W. H.; Newlander, K. A.; Nichols, A.; Parker, M. F.; Peischoff, C. E.; Samanen, J. M.; Uzinskas, I.; Venslavsky, J. W. Direct Design of a Potent Non-Peptide Fibrinogen Receptor Antagonist Based on the Structure and Conformation of a Highly Constrained Cyclic RGD Peptide. J. Am. Chem. Soc. 1993, 115, 8861-8862.
32. 7 Mimetic for the Predicted γ-Turn Conformation Found in Several Constrained RGD Antagonists. J. Med. Chem. 1992, 35, 3970-3972.
33. Egbertson, M. S.; Naylor, A. M.; Hartman, G. D.; Cook, J. J.; Gould, R. J.; Holahan, M. A.; Lynch, Jr., J. J.; Lynch, R. J.; Stranieri, M. T.; Vassallo, L. M. Non-Peptide Fibrinogen Receptor Antagonists. 3. Design and Discovery of a Centrally Constrained Inhibitor. Biorg. Med. Chem. Lett. 1994, 4, 1835-1840.
34. Hirschmann, R.; Sprengeler, P. A.; Kawasaki, T.; Leahy, J. W.; Shakespeare, W. C.; Smith, A. B., III. The First Design and Synthesis of a Steroidal Peptidomimetic. The Potential Value of Peptidomimetics in Elucidating the Bioactive Conformation of Peptide Ligands. J. Am. Chem. Soc. 1992, 114, 9699-9701.
35. McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D.; Somers, T. C.; Thorsett, E. D.; Tischler, M.; Webb, R. R.; Venuti, M. C. From Peptide to Non-Peptide. 2. The de Novo Design of Potent, Non-Peptidal Inhibitors of Platelet Aggregation Based on a Benzodiazepinedione Scaffold. J. Am. Chem. Soc. 1994, 116, 5077-5083.
36. Miller, W. H.; Ali, F. E.; Bondinell, W. E.; Callahan, J. F.; Calvo, R. R.; Eggleston, D. S.; Haltiwanger, R. C.; Huffman, W. F.; Hwang, S.-M.; Jakas, D. R.; Keenan, R. M.; Koster, P. F.; Ku, T. W.; Kwon, C.; Newlander, K. A.; Nichols, A. J.; Parker, M, F.; Samanen, J. M.; Southall, L. S.; Takata, D. T.; Uzinskas, I. N.; Valocik, R. E.; Vasko-Moser, J. A.; Wong, A. S.; Yellin, T. O.; Yuan, C. C. K. Structure-Activity Relationships in 3-Oxo-1,4-Benzodiazepine-2-Acetic Acid GPIIb/IIIa Antagonists. The 2-Benzazepine Series. Bioorg. Med. Chem. Lett. 1996, 6, 2481-2486.
37. Egbertson, M. S.; Hartman, G. D.; Gould, R. J.; Bednar, B.; Bednar, R. A.; Cook, J. J. Gaul, S. L.; Holahan, M. A.; Libby, L. A.; Lynch, J. J.; Lynch, R. J.; Sitko, G. R.; Stranieri, M. T.; Vassallo, L. M. Nonpeptide GPIIb/IIIa Inhibitors. 10. Centrally Constrained Alpha-Sulfonamides are Potent Inhibitor of Platelet Aggregation. Bioorg. Med. Chem. Lett. 1996, 6, 2519-2524.
38. Wityak, J.; Sielecki, T. M.; Pinto, D. J.; Emmett, G.; Sze, J. Y.; Liu, J.; Tobin, E. Wang, S.; Jiang, B.; Ma, P.; Mousa, S. A.; Wexler, R. R.; Olson, R. Discovery of Potent Isoxazoline Glycoprotein IIb/IIIa Receptor Antagonists. J. Med. Chem. 1997, 40, 50-60.
39. Fisher M. J.; Gunn, B. P.; Harms, C. S.; Kline, A. D.; Mullaney, J. T.; Scarborough, R. M.; Skelton, M. A.; Um, S. L.; Utterback, B. G.; Jakubowski, J. A. Dihydro-isoquinolone RGD Mimics. Exploration of the Aspartate Isostere. Bioorg. Med. Chem. Lett. 1997, 7, 2537-2542.
40. Fisher, M. J.; Gunn, B.; Harms, C. S.; Kline, A. D.; Mullaney, J. T.; Nunes, A.; Scarborough, R. M.; Skelton, M. A.; Um, S. L.; Utterback, B. G.; Jakubowski, J. A. Non-Peptide RGD Surrogates Which Mimic a Gly-Asp Beta-Turn are Potent Antagonists of Platelet Glycoprotein IIb-IIIa. J. Med. Chem. 1997, 40, 2085-2101.
41. Scarborough, R. M.; Naughton M. A.; Teng, W.; Rose, J. W.; Phillips, D. R.; Nannizzi, L.; Arfsten, A.; Campbell, A. M.; Charo, I. F. Design of Potent and Specific Integrin Antagonists. J. Biol. Chem. 1993, 268, 1066-1073.
42. Similar compounds have recently been reported in the literature: Okumura, K.; Shimazaki, T.; Aoki, Y.; Yamashita, H.; Tanaka, E.; Banba, S.; Yazawa, K.; Kibayashi, K.; Banno, H. New Platelet Fibrinogen Receptor Glycoprotein IIb-IIIa Antagonists: Orally Active Series of N-Alkylated Amidines with a 6,6-Bicyclic Template. J. Med. Chem. 1998, 41, 4036-4052.
43. Hennige, H.; Kreher, R. P.; Konrad, M.; Jelitto, F. Studies on the Chemistry of Isoindoles and Isoindolenines. Chem. Ber. 1988, 121, 243-252.
44. Shtacher, G.; Erez, M.; Cohen, S. Selectivity in new β-Adrenergic Blocking Agents. (3-Amino-2-hydroxypropoxy)benzamides. J. Med. Chem. 1973, 16, 516-519.
45. Schnur, R. C.; Howard, H. R. 1,2,3,4-Tetrasubstituted isoquinolineacetic acids. Tetrahedron Lett. 1981, 22, 2843-2846.
46. Bryson, T. A. Lactomethylation of Activated Aromatic Carboxylic Acids. Synth. Commun. 1973, 3, 173-175.
47. Cignarella, G.; Barlaocco, D.; Pinna, G. A.; Loriga, M.; Curzu, M. M.; Tofanetti, O.; Germini, M.; Cazzulani, P.; Cavalletti, E. Synthesis and Biological Evaluation of Substituted Benzo[H]-cinnolinones and 3H-Benzo[6,7]cyclohepta[1,2-c]pyridazinones; Higher Homologues of the Antihypertensive and Antithrombotic 5H-Indeno[1,2-c]pyridazinones. J. Med. Chem. 1989, 32, 2277-2282.
48. Cohen, N.; Weber, G. F. Eur. Pat. Appl., EP 129906 A1.
49. (a) Mousa, S. A.; Forsythe, M.; Lorelli, W.; Bozarth, J.; Xue, C. B.; Wityak, J.; Sielecki, T. M.; Olson, R. E.; DeGrado, W.; Kapil, R.; Hussain, M.; Wexler, R.; Thoolen, M. J.; Reilly, T. M. Novel nonpeptide antiplatelet glycoprotein IIb/IIIa receptor antagonist, DMP754: receptor binding affinity and specificity. Cor. Art. Dis. 1996, 7, 767-74.
50. (b) Guth, B. D.; Seewaldt-Becker, E.; Himmelsbach, F.; Weisenberger, H.; Muller, T. H. Antagonism of the GPIIb/IIIa receptor with the nonpeptidic molecule BIBU52: inhibition of platelet aggregation in vitro and antithrombotic efficacy in vivo. J. Cardiovasc. Pharmacol. 1997, 30, 261-72.
51. Hutchinson, J. H.; Cook, J. J.; Brashear, K. M.; Breslin, M. J.; Glass, J. D.; Gould, R. J.; Halczenko, W.; Holahan, M. A.; Lynch, R. J.; Sitko, G. R.; Stranieri, M. T.; Hartman, G. D. Non-Peptide Glycoprotein IIb/IIIa Antagonists. 11. Design and in vivo Evaluation of 3,4-Dihydro-1-(1H)-isoquinolinone-Based Antagonists. J. Med. Chem. 1996, 39, 4583-4591.
52. 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.
53. 3) Antagonists. J. Med. Chem. 1997, 2289-2292.
54. The identity of the arginine isostere has also been shown to play an influential role in the determination of integrin selectivity. For leading references, see: Keenan, R. M.; Miller, W. H.; Lago, M. A.; Ali, F. E.; Bondinell, W. E.; Callahan, J. F.; Calvo, R. R.; Cousins, R. D.; Hwang, S.-M.; Jakas, D. R.; Ku, T. W.; Kwon, C.; Nguyen, T. T.; Reader, V. A.; Rieman, D. J.; Ross, S. T.; Takata, D. T.; Uzinskas, I. N.; Yuan, C. C. K.; Smith, B. R. Bioorg. Med. Chem. Lett. 1998, 3165-3170.
55. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John Wiley and Sons, Inc.: New York, 1967; p 584.
56. Tomita, M.; Minami, S.; Uyeo, S. Schmidt reaction with Benzocycloalkenones. J. Chem. Soc. C 1969, 183-188.
57. Scarborough, R. M.; Rose, J. W.; Naughton, M. A.; Phillips, D. R.; Nannizzi, L.; Arfsten, A.; Campbell, A. M.; Charo, I. F. Characterization of the integrin specificities of disintegrins isolated from American pit viper venoms. J. Biol. Chem. 1993, 268, 1058-1065.
58. Su, T.; Naughton, A. H.; Smyth, M. S.; Rose, J. W.; Arfsten, A. E.; McCowan, J. R.; Jakubowski, J. A.; Wyss, V. L.; Ruterbories, K. J.; Sall, D. J.; Scarborough, R. M. Fibrinogen receptor (GPIIb-IIIa) antagonists derived from 5,6-bicyclic templates. Amidinoindoles, amidinoindazoles and amidinobenzofurans containing the N-α-sulfonamide carboxylic acid function as potent platelet aggregation inhibitors. J. Med. Chem. 1997, 40, 4308-4318.
59. Jakubowski, J. A.; Maraganore, J. M. Inhibition of coagulation and thrombin-induced platelet activities by a synthetic dodecapeptide modeled on the carboxy terminus of hirudin. Blood 1990, 75, 399-406.