Conformational preferences in a benzodiazepine series of potent nonpeptide fibrinogen receptor antagonists

Journal of Medicinal Chemistry

Volumn 42, Issue 4, 1999, Pages 545-559

  Keenan, Richard M ^a   Callahan, James F ^a   Samanen, James M ^a   Bondinell, William E ^a   Calvo, Raul R ^a   Chen, Lichong ^a   DeBrosse, Charles ^a   Eggleston, Drake S ^a   Haltiwanger, R Curtis ^a   Hwang, Shing Mei ^a   Jakas, Dalia R ^a   Ku, Thomas W ^a   Miller, William H ^a   Newlander, Kenneth A ^a   Nichols, Andrew ^a   Parker, Michael F ^a   Southhall, Linda S ^a   Uzinskas, Irene ^a   Vasko Moser, Janice A ^a   Venslavsky, Joseph W ^a   Wong, Angela S ^a   Huffman, William F ^a   more..

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

BENZODIAZEPINE DERIVATIVE; FIBRINOGEN RECEPTOR ANTAGONIST;

ANTICOAGULATION; ARTICLE; CONFORMATIONAL TRANSITION; DRUG CONFORMATION; DRUG POTENCY; DRUG SYNTHESIS; MOLECULAR MODEL; NUCLEAR MAGNETIC RESONANCE; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; THROMBOCYTE AGGREGATION INHIBITION; X RAY CRYSTALLOGRAPHY;

BENZODIAZEPINES; CRYSTALLOGRAPHY, X-RAY; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0033602275     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980166z     Document Type: Article

References (40)

1. Coller, B. S.; Anderson, K.; Weisman, H. F. New antiplatelet agents: platelet GPIIb/IIIa antagonists. Thromb. Haemost. 1995, 74, 302-308.
2. Kieffer, N.; Phillips, D. R. Platelet Membrane Glycoproteins: Functions in Cellular Adhesion and Aggregation. Annu. Rev. Cell. Biol. 1990, 6, 329-357.
3. See: (a) Lefkovits, J.; Plow, E. F.; Topol, E. J. Platelet Glycoprotein IIb/IIIa Receptors in Cardiovascular Medicine. N. Engl. J. Med. 1995, 332, 1553-1559.
4. (b) Samanen, J. Annu. Rep. Med. Chem. 1996, 31, 91-100.
5. D'Souza, S. E.; Ginsberg, M. H.; Plow, E. F. Arginyl-glycyl-aspartic acid (RGD): A Cell Adhesion Motif. Trends Biochem. Sci. 1991, 16, 246-250.
6. Nichols, A. J.; Ruffolo, R. R., Jr.; Huffman, W. H.; Poste, G.; Samanen, J. Trends Pharmacol. Sci. 1992, 13, 413.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. III Antagonists. J. Med. Chem. 1994, 37, 1-8.
13. 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.
14. Muller, G.; Gurrath, M.; Kessler, H. Pharmacophore refinement of gpIIb/IIIa antagonists based on comparative studies of anti-adhesive cyclic and acyclic RGD peptides. J. Comput. Aided. Mol. Des. 1994, 8, 709-730.
15. 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.
16. 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.
17. (a) 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 Family of High Affinity Ligands for GP IIB-IIIa. J. Am. Chem. Soc. 1994, 116, 3207-3219.
18. (b) Wityak, J.; Sielecki, T. M.; Pinto, D. J.; Emmet, 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.
19. 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.
20. (a) 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. 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, 5069-5077.
21. (b) 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.
22. Fisher, M. J.; Gunn, B.; Harms, C. S.; Kline, A. D.; Mullaney, J. T.; Nunes, A.; Scarborough, R. M.; Arfsen, A. E.; Skelton, M. A.; Um, S. L.; Utterback, B. G.; Jacubowski, J. A. Non-Peptide RGD Surrogates Which Mimic a Gly-Asp β-turn: Potent Antagonists of Platelet Glycoprotein IIb-IIIa. J. Med. Chem. 1997, 40, 2085-2101.
23. 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.
24. For recent reviews of the progress in the development of nonpeptide IIb/IIIa antagonists, see ref 3b and: Ojima, I.; Chakravarty, S.; Dong, Q. Antithrombotic agents: from RGD to peptide mimetics. Bioorg. Med. Chem. 1995, 3, 337-360.
25. Callahan, J. F.; Bean, J. W.; Burgess, J. L.; Eggleston, D. E.; 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 C7 Mimetic for the Predicted γ-turn Conformation Found in Several Constrained RGD Antagonists. J. Med. Chem., 1992, 35, 3970-3972.
26. 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.; 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 Structure and Conformation of a Highly Constrained Cyclic RGD Peptide. J. Am. Chem. Soc. 1993, 115, 8861-8862.
27. (a) 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.; 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 (GPIIB/IIIA) Antagonist. Bioorg. Med. Chem. 1994, 2, 897-908.
28. (b) Bondinell, W. E.; et al. Manuscript in preparation.
29. 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.; Koster, P. F.; 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.; Vasko-Moser, J. A.; Valocik, R. E.; Yellin, T. O.; Uzinskas, I.; Venslavsky, J. W.; Wong, A.; 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.
30. Miller, W. H.; Bondinell, W. E.; Callahan, J. F.; Eggleston, D. S.; Huffman, W. F.; Hwang, S. M.; Jakas, D. R.; Keenan, R. M.; Koster, P. F.; Ku, T. W.; Kwon, C. K.; Nichols, A. J.; Samanen, J. M.; Takata, D. T.; Uzinskas, I. N.; Valocik, R. E.; Vasko-Moser, J. A.; Wong, A. S. 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.
31. Bondinell, W. E.; Callahan, J. F.; Huffman, W. F.; Keenan, R. M.; Ku, T. W.; Newlander, K. A.; Samanen, J. M.; Uzinskas, I. N. WO 9414776, July 7, 1994.
32. Miller, W. H.; Newlander, K. A.; Eggleston, D. S.; Haltiwanger, R. C.; Synthesis of a 2-Benzazepine Analogue of a Potent, Nonpeptide GPIIb/IIIa Antagonist. Tetrahedron Lett. 1995, 36, 373-376.
33. For a full description of the in vitro assays, see ref 24a.
34. The intestinal permeability of these compounds was the subject of a recent review; See: Samanen, J. M.; Lee, C.-P.; Smith, P. L.; Bondinell, W.; Calvo, R. R.; Jakas, D. R.; Newlander, K.; Parker, M.; Uzinskas, I.; Yellin, T. O.; Nichols, A. J. The Use of Rabbit Intestinal Permeability as an in vitro Assay in the Search for Orally Active GPIIb/IIIa Antagonists. Adv. Drug Deliv. Rev. 1996, 23, 133-142.
35. For prototypical acyclic nonpeptide fibrinogen receptor antagonists, see: (a) 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.; et al. Non-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitors. J. Med. Chem. 1992, 35, 4640-4642.
36. (b) 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.; Toth, M. V.; Zupec, M. E.; McMackins, D. E.; Adams, S. P.; Miyano, M.; Markos, C. S.; Milton, M. N.; Paulson, S.; Herin, M.; et al. 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.
37. Monte Carlo simulations were done using MacroModel version 6.0 (Department of Chemistry, Columbia University, New York).
38. Minimizations within BatchMin V6.0 (Department of Chemistry, Columbia University, New York) were performed using AMBER*. All force-field equations are identical with those of authentic AMBER from P. Kollman.
39. The biological activity for the benzodiazepine series has been shown to reside in the (S)-configuration at the acetic acid stereocenter, as in L-aspartic acid; see refs 24a and 25.
40. Blackburn, B. K.; Lee, A.; Baier, M.; Kohl, B.; Olivero, A. G.; Matamoros, R.; Robarge, K. D.; McDowell, R. S. From peptide to non-peptide. 3. Atropisomeric GPIIbIIIa antagonists containing the 3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione nucleus. J. Med. Chem. 1997, 40, 717-729.