Non-peptide glycoprotein IIb/IIIa inhibitors. 17. Design and synthesis of orally active, long-acting non-peptide fibrinogen receptor antagonists

Journal of Medicinal Chemistry

Volumn 40, Issue 12, 1997, Pages 1779-1788

  Askew, Benny C ^a   Bednar, Rodney A ^a   Bednar, Bohumil ^a   Claremon, David A ^a   Cook, Jacquelynn J ^a   McIntyre, Charles J ^a   Hunt, Cecila A ^a   Gould, Robert J ^a   Lynch, Robert J ^a   Lynch Jr , Joseph J ^a   Gaul, Stanley L ^a   Stranieri, Maria T ^a   Sitko, Gary R ^a   Holahan, Marie A ^a   Glass, Joan D ^a   Hamill, Terrence ^a   Gorham, Lynn M ^a   Prueksaritanont, Thomayant ^a   Baldwin, John J ^a,b   Hartman, George D ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b PHARMACOPEIA INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FIBRINOGEN; FIBRINOGEN RECEPTOR; FIBRINOGEN RECEPTOR ANTAGONIST; FIBRONECTIN; L 734115; N [(4 METHYLPHENYL)SULFONYL] 3 [[[5,6,7,8 TETRAHYDRO 4 OXO 5 [2 (4 PIPERIDINYL)ETHYL] 4H PYRAZOLO[1,5 A][1,4]DIAZEPIN 2 YL]CARBONYL]AMINO]ALANINE; UNCLASSIFIED DRUG; VITRONECTIN;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DOG; DOSE TIME EFFECT RELATION; DRUG RECEPTOR BINDING; DRUG STRUCTURE; EQUILIBRIUM CONSTANT; FEMALE; HUMAN; MALE; NONHUMAN; ORAL DRUG ADMINISTRATION; RECEPTOR AFFINITY; RECEPTOR BLOCKING; STRUCTURE ACTIVITY RELATION; THROMBOCYTE AGGREGATION INHIBITION;

ADENOSINE DIPHOSPHATE; ANIMALS; AZEPINES; BLOOD PLATELETS; COLLAGEN; DOGS; ENDOTHELIUM, VASCULAR; FIBRINOGEN; FIBRINOLYTIC AGENTS; FIBRONECTINS; HUMANS; MOLECULAR STRUCTURE; PLATELET AGGREGATION INHIBITORS; PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; VITRONECTIN;

EID: 14444287796     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9608117     Document Type: Article

References (44)

1. (a) Falk, E. Unstable Angina with Fatal Outcome, Dynamic Coronary Thrombosis leading to Infarction and/or Sudden Death: Autopsy Evidency of Rerecurrent Mural Thrombosis with Perpheral Embolism Culminating in Total Vascular Occlusion. Circulation 1985, 71, 699.
2. (b) Colman, R. W.; Marder, V. J.; Salzman, E. W.; Hirsch, J. Hemostatis and Thrombosis: Basic Principles and Clinical Practices; Lippincott Publishers: Philadelphia, PA.
3. Levin, D. C; Fallon, J. T.; Significance of the Angiographic Morphology of Localized Coronary Stenosis: Histopathologic Correlations. Circulation 1982, 66, 316-320.
4. Fitzgerald, D. J.; Roy, L.; Catella, F.; Fitzgerald, G. G. Platelet Activation in Unstable Cornary Disease. N. Engl. J. Med. 1986, 315, 983-989.
5. Splawinski, B; Kuzniar, J.; Splawinski, J. Platelet Aggregation and Deaggregation in Unstable Cornary Disease. Med. Actual. 1991, 27, 83-106.
6. Marguerie, G. A.; Plow, E. F.; Edginton, T. S. Human Platelets Possess an Inducible and Saturable Receptor Specific for Fibrinogen. J. Biol. Chem. 1979, 254, 5357-5363.
7. Peerscke, E. I.; Zucker, M. B.; Grant, R. A.; Egan, J. J.; Johnson, M. M. Correlation Between Fibrinogen Binding to Human Platelets and Platelet Aggregability. Blood 1980, 55, 841-847.
8. Hawiger, J.; Klozewiak, M.; Bednarek, M. A.; Timmonms, S. Platelet Receptor Recognition Domains on the a Chain of Human Fibrinogen: Structure, Function and Analysis. Biochemistry 1989, 28, 2909-2914.
9. Plow, E. F.; Piersbascher, M. D.; Ruoslathi, E.; Margurie, G. A.; Ginsberg, M. H. The Effect of Arg-Gly-Asp-Containing Peptides on Fibrinogen and von Willebrand Factor binding to Platelets. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 8057-8061.
10. Gan, Z.-R.; Gould, R. G.; Jacobs, J. W.; Freidman, P. A.; Polokoff, M. A. Echistatin, A Potent Platelet Aggregation Inhibitor from the Venom of the Viper, Echis Carinatus. J. Biol. Chem. 1988, 263, 19827-19823.
11. Gould, R. J. ; Polokoff, M. A.; Freidman, P. A.; Huang, T.-F.; Holt, J. C.; Cook, J. J.; Niewiarowski, S. Disintegrins, : a Family of Integrin Inhibitory Proteins from Viper Venoms. Proc. Soc. Exp. Biol. Med. 1990, 195, 168-171.
12. Nutt, R. F.; Brady, S. F.; Sisko, J. T.; Ciccarone, T. M.; Colton, C. D.; Levy, M. R.; Gould, R. J.; Zhang, 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 (proceedings of the 21st European Peptide Symposium); Giralt, E., Andreu, D., Eds.; ESCOM: Leiden, 1991; pp 784-786.
13. Barker, P. L.; Bullens, S.; Bunting, S.; Burdick, D. J.; Chan, K. S.; Diesher, T.; Eigenbrot, C.; Gadek, T. R.; Gantoz, R.; Lipari, M. T.; Muir, C. D.; Pitti, R. M.; Padua, A.; Quan, C. Stanley, M. Stuble, M.; Tom, J. Y. K.; Burnier, J. P. Cyclic RGD Peptide Analogues as Antiplatelet Antithrombotics. J. Med. Chem. 1992, 35, 2040-2048.
14. 3 Antagonists. J. Med. Chem. 1994, 37, 1-9.
15. For recent reviews, see: (a) Weller, T. Alig, L. Hureler-Muller, M.; Kouns, W. C.; Steiner, B. Fibrinogen Receptor Antagonists: A Novel Class of Promising Antithrombotics. Drugs Future 1994, 19, 461-476.
16. (b) Austel, V.; Himmelsbach, F.; Muller, T. Non-peptide Fibrinogen Receptor Antagonists. Drugs Future 1994, 19, 461-476.
17. Cook, N. S.; Kottirisch, G. Zerwes, H.-G. Platelet Glycoprotein IIb/IIIa Antagonists. Drugs Future 1994, 19, 135,159.
18. (a) Ku, T. W.; Ali, F. E.; Barton, L. S.; Bean, J. W.; Bondinell, W. E.; Burges, J. L. Callahan, J. F.; Calco, R. R.; Chen. L.; Eggleston, 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.; Peishoff, C. E.; Samanen, J. M. ; Uzinskas, I.; Venslavsky, J. W. Direct Design of a Potent Non-peptide Fibrinogen Receptor Antagonist Based on the Strucutre and Conformation of a Highly Constrained Cyclic RGD Peptide. J. Am. Chem. Soc. 1993, 115, 8861-8862.
19. (b) McDowell, R. S.; Gadek, 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.; Webb, T. R.; Burnier, 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, 5069-5076.
20. (c) McDowell, R. S.; Blackburn, B. K.; Gadek, T. R.; McGee, L. R.; Rawson, T.; Reynolds, M. E.; Robarge, K. D. Sommers, T. C.; Thorsett, E. D.; Tischler, M.; Webb, T. 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.
21. (d) Ku, T. W.; Miller W. H.; Bondinell, W. E.; Erhard, K. F.; Keenan, R. M.; Nichols, A.; Peishoff, C. E.; Samanen, J. M.; Wong, A. S.; Huffman, W. F.; Potent Non-Peptide Fibrinogen Receptor Antagonists Which Present an Alternate Pharmacophore. J. Med. Chem. 1995, 38, 9-12.
22. (e) 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. 1995, 39, 2118-2122.
23. (f) Weller, T.; Alig, L. Beresini, M.; Blackburn, B.; Bunting, S.; Hadváry, P.; Müller, H. M.; Knopp, D.; Levet-Traift, B.; Lipari, M. T.; Modi, N. B.; Müller, M.; Refino, C. J.; Schmitt, M.; Schönholzer, P.; Weiss, S.; Steiner, B. Orally Active Fibrinogen Receptor Antagonists. 2. Amidoximes as Prodrugs of Amidines. J. Med. Chem. 1996, 39, 3139-3147.
24. (a) 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.; Manno, P. D.; Naylor, A. M.; Prugh, J. D.; Ramjit, D. R.; Sitko, G. R.; Smith, R. S.; Turchi, L. M.; Zhang, G. X. Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic of Arg-Gly-Asp. J. Med. Chem. 1994, 37, 2535-2551.
25. (b) Egbertson, M. S.; Naylor, A. M.; Hartman, G. D.; Cook, J. J.; Gould, R. J.; Holohan M. A. Non-Peptide Fibrinogen Receptor Antagonists. 3. Design and Discovery of a Centrally Constrained Inhibitor. Bioorg. Med. Chem. Lett. 1994, 4, 1835-1840.
26. (c) Naylor, A. M.; Egbertson, M. S.; Vasallo, L. M.; Birchenough, L. A.; Zhang, G. X.; Gould, R. J. Non-Peptide Fibrinogen Receptor Antagonists. 4. Proposed Three-Diminisional Binding Requirements In Centrally Constrained Inhibitors. Bioorg. Med. Chem. Lett. 1994, 4, 1841-1845.
27. (d) 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. 8. Design and Synthesis Centrally Constrained Non-Peptide Fibrinogen Receptor Antagonists. Bioorg. Med. Chem. Lett. 1995, 5 , 475-480.
28. (a) 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. Non-Peptide GPIIb/IIIa Inhibitors. 10. Centrally Constrained Alpha-Sulfonamides are Potent Inhibitors of Platelet Aggregation. Bioorg. Med. Chem. Lett. 1996, 6, 2519-2524.
29. (b) Halczenko, W.; Cook, J. J.; Holahan, M. A.; R. J.; Sitko, G. R.; Stranieri, M. T.; Zhang, G.; Lynch, R. J.; Lynch, J. J.; Gould, R. J.; Hartman, G. D. Non-Peptide GPIIb/IIIa Inhibitors. 11. Potent and Orally Active Centrally Constrained Thieno[2,3-c]-Pyridinones. Bioorg. Med. Chem. Lett. 1996, 6, 2771-2776.
30. (c) 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. 13. Design and Synthesis of Orally Active Pyrazolopiperazinone Non-Peptide Fibrinogen Receptor Antagonists. Bioorg. Med. Chem. Lett., in press.
31. Xue, C.-B.; Raafalski, M.; Roderick, J.; Eyermann, C. J.; Mousa, S.; Olsen, R. E.; DeGrado, W. F., Design, Synthesis and In Vitro Activities of a Series of Benzimidazole/Benzoxazole Glycloprotein IIb/IIIa Inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 339-344.
32. Garegg, P. J.; Samuelsson, B. Novel Reagent System for Converting a Hydroxy-group into an lodo-group in Carbohydrates with Inversion of Configuration. J. Chem. Soc., Chem Commun. 1979, 978.
33. Egbertson, M. S.; Bednar, B.; Bednar, R. A.; Hartman, G. D.; Gould, R. J.; Lynch, R. J.; Vassallo, L. M.; Young, S. D. Non-Peptide Glycoprotein IIb/IIIa Inhibitors. 9. Centrally Constrained Alpha-Sulfonamides are Useful Tools for Exploring Platelet Receptor Function. Bioorg. Med. Chem. Lett. 1998, 6, 1415-1420.
34. Bednar, R. A.; Gaul, S. L.; Hamill, T.; Egbertson, M. S.; Hartman, G. D.; Gould, R. J.; Bednar, B. Selectivity of GP IIb/IIIa Antagonists in Binding to Activated and Unactivated Forms of Purified GP IIb/IIIa and to Resting and Activated Platelets. Blood, in press.
35. 3H]-5 will be published elsewhere. For a description of its use in measuring binding affinities to resting human platelets see the In Vitro Pharmacology section of the Experimental Section.
36. Bednar, B.; Cunnigham, M. E.; McQueney, P. A.; Egbertson, M. S.; Askew, B. C.; Bednar, R. A.; Hartman, G. D.; Gould, R. J. Flow Cytometric Measurement of Kinetic and Equilibrium Binding Parameters of RGD Ligands in Binding to GPIIb/IIIa on Platelets. Cytometry, in press.
37. Duggan, M. E.; Naylor-Olsen, A. M.; Perkins, J. J.; Anderson, P. S.; Chang, C. T.-C.; Cook, J. J.; Gould, R. G.; Ihle, N. C.; Hartman, G. D.; Lynchn 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 Antagoniost. J. Med. Chem. 1995, 38, 3332-3341.
38. Prueksaritanont, T.; Stranieri, M. T.; Hand, E.l.; Ellis, J. D.; Holahan, M. A.; Sitko, G. R.; Cook. J. J. Effects of Pentobarbital on the Pharmacokinetics and Pharmacodynamics of L-734,217, a Potent Fibrinogen Receptor Antagonist in Dogs. Biopharm. Drug Disp., in press.
39. (a) Bednar, R. A.; Gaul, S. L.; Cook, J. J.; Askew, B. C.; Hartman, G. D.; Gould, R. J.; Bednar, B.; Novel Mechanism for Long Acting GP IIb/IIIa Antagonists. Circulation 1996, 94, I-98
40. (b) Prueksaritanont, T.; Gorham, L. M.; Naue, J. A.; Hamill. T. Askew, B. C.; Vyas, K. P.; Disposition of L-738,167, a Potent and Long Acting Fibrinogen Receptor Antagonist in Dogs: Dose-dependent Pharmacokinetics. Drug Metab. Dispos. 1997, 25, 355-361.
41. (a) Cook, J. J.; Sitko, G. R.; Holahan, M. A.; Stranieri, M. T.; Glass, J. D. Askew, B. C.; McIntyre, C. J.; Claremon, D. A.; Baldwin, J. J.; Hartman, G. D.; Gould, R.J.; Lynch, J. J. Non-Peptide Glycoprotein IIb/IIIa Inhibitors. 14. Oral Antithrombotic Efficacy of L-738,167 in a Conscious Canine Model of Coronary Artery Electrolytic Injury. Circulation, in press.
42. (b) Cook, J. J.; Sitko, G. R.; Holahan, M. A.; Stranieri, M. T.; Glass, J. D. Askew, B. C.; Hartman, G. D.; Gould, R. J.; Lynch, J. J. Non-Peptide Glycoprotein IIb/IIIa Inhibitors. 15. Antithrombotic Efficacy of L-738,167, A Long-Acting GPIIb/IIIa Antagonist, Correlates with Inhibition of ADP-Induced Platelet Aggregation But Not With Bleeding Time Prolongation. J. Pharmacol. Exp. Ther., in press.
43. Albeida, S. M.; Daise, M.; Levine, E. M.; Buck, C. A. Identification and Chacterization of Cell-Stratum Adhesion Reseptors on Cultured Human Endothelial Cells. J. Clin. Invest. 1989, 83, 1992.
44. Kouns, W. C.; Hadvary, P.; Haering, P.; Steiner, B.; Conformational Modulation of Purified Glycoprotein GPIIb-IIIa Allows Proteolytic Generation of Active Fragments from Either Active or Inactive GP IIb-IIIa. J. Biol. Chem. 1992, 267, 18844-18851.