Non-peptide RGD surrogates which mimic a Gly-Asp β-turn: Potent antagonists of platelet glycoprotein IIb-IIIa

Journal of Medicinal Chemistry

Volumn 40, Issue 13, 1997, Pages 2085-2101

  Fisher, Matthew J ^a   Gunn, Bruce ^a   Harms, Cathy S ^a   Kline, Allen D ^a   Mullaney, Jeffrey T ^a   Nunes, Anne ^a   Scarborough, Robert M ^b   Arfsten, Ann E ^b   Skelton, Marshall A ^a   Um, Suzane L ^a   Utterback, Barbara G ^a   Jakubowski, Joseph A ^a  

^a ELI LILLY AND COMPANY   (United States)

^b MILLENNIUM PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 [[4 (AMINOMETHYL)BENZOYL]AMINO] 3,4 DIHYDRO 1 OXO 2(1H) ISOQUINOLINEACETIC ACID MONO(TRIFLUOROACETATE); 6 [[[4 (AMINOIMINOMETHYL)PHENYL]AMINO]CARBONYL] 3,4 DIHYDRO 1 OXO 2(1H) ISOQUINOLINEACETIC ACID MONO(TRIFLUOROACETATE); FIBRINOGEN RECEPTOR; FIBRINOGEN RECEPTOR ANTAGONIST; G 6249; HEPTAPEPTIDE; QUINOLONE DERIVATIVE; SB 208651; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DRUG POTENCY; DRUG SYNTHESIS; ENZYME LINKED IMMUNOSORBENT ASSAY; HUMAN; HUMAN CELL; PROTON NUCLEAR MAGNETIC RESONANCE; RECEPTOR AFFINITY; THROMBOCYTE; THROMBOCYTE AGGREGATION;

ASPARTIC ACID; DRUG DESIGN; ENZYME-LINKED IMMUNOSORBENT ASSAY; GLYCINE; HUMANS; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR MIMICRY; OLIGOPEPTIDES; PLATELET AGGREGATION; PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX; PROTEIN STRUCTURE, SECONDARY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 14444269454     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9701076     Document Type: Article

References (77)

1. 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.
2. Phillips, D. R.; Charo, I. F.; Parise, L. V.; Fitzgerald, L. A. The Platelet Membrane Glycoprotein IIb/IIIa Complex. Blood 1988, 71, 831-843.
3. Phillips, D. R.; Charo, I. F.; Scarborough, R. M. GPIIb-IIIa: The Responsive Integrin. Cell 1991, 65, 359-362.
4. Coller, B. S. Platelets and Thrombolytic Therapy. N. Engl. J. Med. 1990, 322, 33-42.
5. Hamm, C. W.; Bleifield, W.; Kupper, W.; Lorens, R. L.; Wever, P.; Wober, W. Biochemical Evidence of Platelet Activation in Patients with Persistent Unstable Angina. J. Am. Coll. Cardiol. 1987, 10, 998-1004.
6. For a recent reviews, see: (a) Samanen, J. Annu. Rep. Med. Chem. 1996, I, 91-100. (b) Ogima, I.; Chakravarty, S.; Dong, Q.; Antithrombotic Agents: From RGD to Peptide Mimetics. Bioorg. Med. Chem. 1995, 3, 337-360.
7. For a recent reviews, see: (a) Samanen, J. Annu. Rep. Med. Chem. 1996, I, 91-100. (b) Ogima, I.; Chakravarty, S.; Dong, Q.; Antithrombotic Agents: From RGD to Peptide Mimetics. Bioorg. Med. Chem. 1995, 3, 337-360.
8. Kroll, M. H.; Schaffer, A. I. Biochemical Mechanisms of Platelet Activation. Blood 1989, 74, 1181-1195.
9. Lefkovits, J.; Plow, E. F.; Topol, E. J. Platelet Glycoprotein IIb/ IIIa Receptors in Cardiovascular Medicine. N. Engl. J. Med. 1995, 332, 1553-1559.
10. 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.
11. 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.
12. 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.
13. +2 dependant 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.
14. For leading references, see: D'Souza, S. E.; Ginsberg, M. H.; Plow, E. F. Arginyl-glycyl-aspartic acid (RGD): A Cell Adhesion Motif. Trends Biochem. Sci. 1991, 76, 246-250.
15. Greenspoon, N.; Hershkoviz, R.; Alon, R.; Varon, D.; Shenkman, B.; Marx, G.; Federman, S.; Kapustina, G.; Liker, O. Biochemistry 1993, 32, 1001-1008.
16. Pierschbacher, M. D.; Ruoslahti, E. Influence of Stereochemistry on the Sequence Arg-Gly-Asp-Xaa on Binding Specificity in Cell Adhesion. J. Biol. Chem. 1987, 262, 17294-17298.
17. 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. (b) Shebuski, R. J. Annu. Rep. Med. Chem. 1991, 26, 93.
18. 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. (b) Shebuski, R. J. Annu. Rep. Med. Chem. 1991, 26, 93.
19. 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, Proceeding of the 21st European Peptide Symposium; Giralt, E., Andreu, D., Eds.; ESCOM Science Publishers: Leiden, 1990; pp 781-783.
20. 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.
21. 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
22. 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 12th American Peptide Symposium; Smith, J. A., Rivier J. E., Eds.; ESCOM: Leiden, 1992; pp 761-762.
23. 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 Twelfth American Peptide Symposium; Smith, J. A., River, J. E., Eds.; ESCOM: Leiden, The Netherlands, 1992; pp 914-916.
24. 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.
25. 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.
26. 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.
27. β-βIII Antagonists.' J. Med. Chem. 1994, 37, 1-8.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. 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.
34. 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.
35. 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(Anrinoimino-methyl)Phenyl]-1-Piperazinyl-1-Piperidineacetic acid as a Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885.
36. 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 GP IIb-IIIa receptor. J. Med. Chem. 1993, 36, 1811-1819.
37. 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 GP IIb-IHa receptor. J. Med. Chem. 1992, 35, 4914-4917.
38. 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.
39. Callahan, J. F.; Bean, J. W.; Burgess, J. L.; Eggelston, D. S.; Hwang, S. M.; Kopple, K. D.; Koster, P. f.; Nichols, A.; Peishoff, C. E.; Samanen, J. M.; Vasko, J. A.; Wong, A;. Huffman, W. F. Design and Synthesis of a Cv Mimetic for the Predicted γ-Turn Conformation Found in Several Constrained RGD Antagonists. J. Med. Chem, 1992, 35, 3970-3972.
40. 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.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. (a) Mickos, H.; Bahr, J.; Bjorn, L. Three-dimensional structure of the RGD (Arg-Gly-Asp) adhesion sequence of fibronectin; NMR studies of the peptides RGDS and GRGDSP. Acta Chem. Scand, 1990, 44, 161-164.
47. (b) Reed, J.; Hull, W. E.; Lieth, C.-W.; Kubler, D.; Suhai, S.; Kinzel, V.; Secondary structure of the Arg-Gly-Asp recognition site in proteins involved in the cell-surface adhesion. Eur. J. Biochem. 1988, 178, 141-154.
48. Chen, Y.; Pitzenberger, S. M.; Garsky, V. M.; Lumma, P. K.; Sanyal, G.; Baum, J. Proton NMR Assignments and Secondary Structure of the Snake Venom Protein Echistatin. Biochemistry 1991, 30, 11625-11636.
49. Saudek, V.; Atkinson, A.; Pelton, J. T. Three Dimensional Structure of Echistatin, the Smallest Active RGD Protein. Biochemistry 1991, 30, 7369-7372.
50. McDowell, R. S.; Gadek, T. R. Structural Studies of Potent Constrained RGD Peptides. J. Am. Chem. Soc. 1992, 114, 9245-9253.
51. Peishoff, C. E.; Ali, F. E.; Bean, J. W.; Calvo, R.; D'Ambrosio, C. A.; Eggleston, D. S.; Hwang, S. M.; Kline, T. P.; Koster, P. F.; Nichols, A.; Powers, D.; Romoff, T.; Samanen, J. M.; Stadel, J.; Vasko, J. A.; Kopple, K. D. Investigation of Conformational Specificity at GPIIb/IIIa: Evaluation of Conformationally Constrained RGD Peptides J. Med. Chem. 1992, 35, 3962-3969.
52. Kopple, K. D.; Baures, P. W.; Bean, J. W.; D'Ambrosio, C. A.; Hughes, J. L.; Peishoff, C. E.; Eggleston, D. S. Conformations of Arg-Gly-Asp Containing Heterodetic Cyclic Peptides: Solution and Crystal Studies. J. Am. Chem. Soc. 1992, 114, 9615-9623.
53. Bach, A. C., II; Eyermann, C. J.; Gross, J. D.; Bower, M. J.; Harlow, R. L.; Weber, P. C., DeGrado, W. F. Structural Studies of a Family of High Affinity Ligands for GP IIB-IIIa. J. Am. Chem. Soc. 1994, 116, 3207-3219.
54. McDowell, R. S.; Gadeck, T. R.; Barker, P. L.; Burdick, D. J.; Chan, K. S.; Quan, C. L.; Skelton, N.; Struble, M.; Thorsett, E. D.; Tischler, M.; Tom, J.Y. K.; Webb, T. R.; Burnler, J. P. From Peptide to Non-Peptide. 1. The Elucidation of a Bioactive Conformation of the Arginine-Glycine-Aspartic Acid Recognition Sequence. J. Am. Chem. Soc. 1994, 116, 5069-5067.
55. Wuthrich, K. NMR of Proteins and Nucleic Acids; Wiley-Interscience, New York, 1986.
56. Ranee, M. Improved Techniques for Homonuclear Rotating-Frame and Isotropic Mixing Experiments J. Magn. Reson. 74, 557-564.
57. Isoquinolone-containing GPIIb/IIIa inhibitors have been recently described: (a) Samanen, J. International Patent Application, WO 94/29273, December 22, 1994. (b) 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 and Ethyl Ester Prodrugs. J. Med. Chem. 1996, 39, 4583-4591.
58. Isoquinolone-containing GPIIb/IIIa inhibitors have been recently described: (a) Samanen, J. International Patent Application, WO 94/29273, December 22, 1994. (b) 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 and Ethyl Ester Prodrugs. J. Med. Chem. 1996, 39, 4583-4591.
59. Tomita, M.; Minami, S.; Shinsaku, M.; Uyeo, S. The Schmidt Reaction with Benzocycloalkenones. J. Chem. Soc. C 1969, 183-186.
60. Bergeron, R. J.; McManis, J. F. Total Synthesis of (±)-15-Deoxyspergulin. J. Org. Chem. 1987, 52, 1700-1703.
61. Hughes, D. L. The Mitsunobu reaction. Org. React. 1992, 42, 335-656.
62. Wagner, G.; Voigt, B.; Vieweg, H. Synthesis of Nα-(Arylsulfonyl-glycyljamidno-phenylalaninamides as Highly Active Inhibitors of Thrombin. Pharmazie 1984, 39, 226-230.
63. Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. A convenient Synthesis of Ethynylarenes and Diethynylarenes. Synthesis 1980, 627-631.
64. Chen, Q.-Y.; Yang, Z.-Y. Palladium-Catalyzed Reaction of Phenyl Fluoroalkanesulfonates with Alkynes and Alkenes. Tettrahedron Lett. 1986, 27, 1171.
65. For leading references, see: Cabri, W.; Candiani, I. Recent Developments and New Perspectives in the Heck Reaction. Acc. Chem. Res. 1995, 28, 2-7.
66. Shioiri, T.; Ninomiya, K.; Yamada, S. Diphenylphosphoryl Azide. A New Convenient Reagent for a Modified Curtius Reaction and for the Peptide Synthesis. J. Am. Chem. Soc. 1972, 94, 6203-6205.
67. Tung, J. S.; Jakubowski, J. A.; Heath, W. F.; Utterback, B. G.; Herron, D. K, Correlation of Molecular Shape With GPIIb/IIIa Receptor Antagonist Activity in RGD Peptides. Receptor 1993, 343-356.
68. Muller, G.; Gurrath, M.; Kessler, H.; Timpl, R. Dynamic Forcing, a Method for Evaluating Activity and Selectivity Profiles of RGD (Arg-Gly-Asp) Peptides. Agnew. Chem., Int. Ed. Engl. 1992, 31, 326-328.
69. 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.
70. Samanen, J. M.; Ali, F. E.; Barton, L. S.; Bondinell, W. E.; Burgess, J. L.; Callahan, J. F.; Calvo, R. R.; Chen, W.; Chen, L.; Erhard, K.; Feuerstein, G.; Heys, R.; Hwang, S.-M.; Jakas, D. R.; Keenan, R, M.; Ku, T. W.; Kwon, C.; Lee, C.-P.; Miller, W. H.; Newlander, K. A.; Nichols, A.; Parker, M.; Peishoff, C. E.; Rhodes, G.; Ross, S.; Shu, A.; Simpson, R.; Takata, D.; Yellin, T. O.; Uzsinskas, I.; Venslavsky, J. W.; Yuan, C.-K.; Huffman, W. F. Potent, Selective, Orally Active 3-Oxo-1,4-benzodiazepine GPIIb/IIIa Integrin Antagonists. J. Med. Chem. 1996, 39, 4867-4870.
71. While apparently not designed as Gly-Asp mimics, other isoquinolone-containing inhibitors which utilize a 2,6 substitution patterns have been described. See ref 54b.
72. Perhaps the best evidence for the promiscuous nature of GPIIb-IIIa can be found by surveying the variety of structural types contained in known inhibitors. See refs 27-42.
73. Ranee, M.; Sorensen, O. W.; Bodenhausen, G.; Wagner, G.; Ernst, R. R.; Wuthrich, K. Biochem. Biophys. Res. Commun. 1983, 113, 967-974.
74. Braunschweiler, L.; Ernst, R. R. Coherence Transfer by Isotropic Mixing - Application to Proton Correlation Spectroscopy J. Magn. Reson. 1983, 53, 521-528.
75. Rucker, S. P.; Shaka, A. Broad-Band Homonuclear Cross Polarization in 2D NMR using DIPSI-2. J. Mol. Phys. 1989, 68, 509-517.
76. 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.
77. Jakubowski, J. A,; Maraganore, J. M. Inhibition of coagulation and thrombin-induced platelet activities by a synthetic dodecapeptide modelled on the carboxy terminus of hirudin. Blood 1990, 75, 399-406.