Use of conformationally restricted benzamidines as arginine surrogates in the design of platelet GPIIb-IIIa receptor antagonists

Journal of Medicinal Chemistry

Volumn 40, Issue 18, 1997, Pages 2843-2857

  Sall, Daniel J ^a   Arfsten, Ann E ^b   Bastian, Jolie A ^a   Denney, Michael L ^a   Harms, Cathy S ^a   McCowan, Jefferson R ^a   Morin Jr , John M ^a   Rose, Jack W ^b   Scarborough, Robert M ^b   Smyth, Mark S ^b   Um, Suzane L ^a   Utterback, Barbara G ^a   Vasileff, Robert T ^a   Wikel, James H ^a   Wyss, Virginia L ^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

4 NITROPHENYL PHOSPHATE; ADENOSINE DIPHOSPHATE; ALKALINE PHOSPHATASE; ARGININE DERIVATIVE; ARGINYLGLYCYLASPARTIC ACID; AVIDIN; BENZAMIDINE DERIVATIVE; BENZOFURAN DERIVATIVE; BICYCLO COMPOUND; BOVINE SERUM ALBUMIN; FIBRINOGEN; FIBRINOGEN RECEPTOR ANTAGONIST; HUMAN SERUM ALBUMIN; VITRONECTIN RECEPTOR;

ARTICLE; DRUG CONFORMATION; DRUG DESIGN; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; ENZYME LINKED IMMUNOSORBENT ASSAY; HYDROGEN BOND; HYDROPHILICITY; LIPOPHILICITY; STRUCTURE ACTIVITY RELATION; THROMBOCYTE AGGREGATION INHIBITION; THROMBOCYTE RICH PLASMA;

ARGININE; BENZAMIDINES; ENZYME-LINKED IMMUNOSORBENT ASSAY; FIBRINOGEN; HUMANS; INDICATORS AND REAGENTS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 15144354433     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970020k     Document Type: Article

References (63)

1. Preliminary accounts of this work have been presented: (a) Sall, D. J.; Arfsten, A. E.; Berry, D. R.; Denney, M. L.; Harms, C. S.; McCowan, J. R; Ray, J. K.; Scarborough, R. M.; Um, S. L.; Utterback, B. G.; Jakubowski, J. A. Platelet Glycoprotein IIb-IIIa Receptor (GPIIb-IIIa) Antagonists Derived from Amidinoindoles. Bioorg. Med. Chem. Lett. 1996, 6, 81-86. (b). McCowan, J. R.; Arfsten, A.; Berry, D. R.; Denney, M. L.; Harms, C. S.; Jakubowski, J.; Ray, J. K.; Rose, J. W.; Sall, D. J.; Scarborough, R. M.; Smyth, M. S.; Um, S. L.; Utterback, B. G. Platelet Glycoprotein IIb-IIIa Receptor (GP IIb-IIIa) Antagonists Derived from 6,5-Templates. Part I: Generation of a Lead and Template Modifications. 210th American Chemical Society National Meeting, Chicago, IL, 1995; MEDI 47. (c) McCowan, J. R.; Arfsten, A.; Denney, M. L.; Harms, C. S.; Jakubowski, J.; Sall, D. J.; Scarborough, R. M.; Um, S. L.; Utterback, B. G. Platelet Glycoprotein IIb-IIIa Receptor (GP IIb-IIIa) Antagonists Derived from 6,5-Templates. Part II: Modifications Proximal to the Carboxylic Acid. 210th American Chemical Society National Meeting, Chicago, IL, 1995; MEDI 48.
2. Preliminary accounts of this work have been presented: (a) Sall, D. J.; Arfsten, A. E.; Berry, D. R.; Denney, M. L.; Harms, C. S.; McCowan, J. R; Ray, J. K.; Scarborough, R. M.; Um, S. L.; Utterback, B. G.; Jakubowski, J. A. Platelet Glycoprotein IIb-IIIa Receptor (GPIIb-IIIa) Antagonists Derived from Amidinoindoles. Bioorg. Med. Chem. Lett. 1996, 6, 81-86. (b). McCowan, J. R.; Arfsten, A.; Berry, D. R.; Denney, M. L.; Harms, C. S.; Jakubowski, J.; Ray, J. K.; Rose, J. W.; Sall, D. J.; Scarborough, R. M.; Smyth, M. S.; Um, S. L.; Utterback, B. G. Platelet Glycoprotein IIb-IIIa Receptor (GP IIb-IIIa) Antagonists Derived from 6,5-Templates. Part I: Generation of a Lead and Template Modifications. 210th American Chemical Society National Meeting, Chicago, IL, 1995; MEDI 47. (c) McCowan, J. R.; Arfsten, A.; Denney, M. L.; Harms, C. S.; Jakubowski, J.; Sall, D. J.; Scarborough, R. M.; Um, S. L.; Utterback, B. G. Platelet Glycoprotein IIb-IIIa Receptor (GP IIb-IIIa) Antagonists Derived from 6,5-Templates. Part II: Modifications Proximal to the Carboxylic Acid. 210th American Chemical Society National Meeting, Chicago, IL, 1995; MEDI 48.
3. Preliminary accounts of this work have been presented: (a) Sall, D. J.; Arfsten, A. E.; Berry, D. R.; Denney, M. L.; Harms, C. S.; McCowan, J. R; Ray, J. K.; Scarborough, R. M.; Um, S. L.; Utterback, B. G.; Jakubowski, J. A. Platelet Glycoprotein IIb-IIIa Receptor (GPIIb-IIIa) Antagonists Derived from Amidinoindoles. Bioorg. Med. Chem. Lett. 1996, 6, 81-86. (b). McCowan, J. R.; Arfsten, A.; Berry, D. R.; Denney, M. L.; Harms, C. S.; Jakubowski, J.; Ray, J. K.; Rose, J. W.; Sall, D. J.; Scarborough, R. M.; Smyth, M. S.; Um, S. L.; Utterback, B. G. Platelet Glycoprotein IIb-IIIa Receptor (GP IIb-IIIa) Antagonists Derived from 6,5-Templates. Part I: Generation of a Lead and Template Modifications. 210th American Chemical Society National Meeting, Chicago, IL, 1995; MEDI 47. (c) McCowan, J. R.; Arfsten, A.; Denney, M. L.; Harms, C. S.; Jakubowski, J.; Sall, D. J.; Scarborough, R. M.; Um, S. L.; Utterback, B. G. Platelet Glycoprotein IIb-IIIa Receptor (GP IIb-IIIa) Antagonists Derived from 6,5-Templates. Part II: Modifications Proximal to the Carboxylic Acid. 210th American Chemical Society National Meeting, Chicago, IL, 1995; MEDI 48.
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18. For recent reviews, see: (a) Blackburn, R. K.; Gadek, T. R. Glycoprotein IIbIIIa Antagonists. Ann. Rep. Med. Chem. 1993, 28, 79-88. (b) Cook, N. S.; Kottirsch, G.; Zerwes, H.-G. Platelet Glycoprotein IIb/IIIa Antagonists. Drugs Future 1994, 19, 135-139. (c) Weller, T.; Alig, L.; Muller, M. H.; Kouns, W. C.; Steiner, B. Fibrinogen Receptor Antagonists - A Novel Class of Promising Antithrombotics. Drugs Future 1994, 19, 461-476.
19. For recent reviews, see: (a) Blackburn, R. K.; Gadek, T. R. Glycoprotein IIbIIIa Antagonists. Ann. Rep. Med. Chem. 1993, 28, 79-88. (b) Cook, N. S.; Kottirsch, G.; Zerwes, H.-G. Platelet Glycoprotein IIb/IIIa Antagonists. Drugs Future 1994, 19, 135-139. (c) Weller, T.; Alig, L.; Muller, M. H.; Kouns, W. C.; Steiner, B. Fibrinogen Receptor Antagonists - A Novel Class of Promising Antithrombotics. Drugs Future 1994, 19, 461-476.
20. For recent reviews, see: (a) Blackburn, R. K.; Gadek, T. R. Glycoprotein IIbIIIa Antagonists. Ann. Rep. Med. Chem. 1993, 28, 79-88. (b) Cook, N. S.; Kottirsch, G.; Zerwes, H.-G. Platelet Glycoprotein IIb/IIIa Antagonists. Drugs Future 1994, 19, 135-139. (c) Weller, T.; Alig, L.; Muller, M. H.; Kouns, W. C.; Steiner, B. Fibrinogen Receptor Antagonists - A Novel Class of Promising Antithrombotics. Drugs Future 1994, 19, 461-476.
21. During the course of this work a number of potent and selective GPIIb-IIIa receptor antagonists were described using benzamidine as an arginine surrogate. (a) Zablocki, J. A.; Miyano, M.; Garland, R. B.; Pireh, D.; Schretzman, L. A.; Rao, S. N.; Lindmark, R. J.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interaction. J. Med. Chem. 1995, 38, 2378-2394. (b) Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B. B.; Szalony, J. A.; Haas, N. F.; King, L. K.; Zablocki, J. A.; Keller, B. T.; Broschat, K.; Engleman, V. W.; Herin, M.; Jacqmin, P.; Feigen, L. P. SC-54684A: An Orally Active Inhibitor of Platelet Aggregation. Circulation, 1995 91, 403-410. (c) Himmelsbach, F.; Austel, V.; Guth, B.; Linz, G.; Muller, T. H.; Piper, H.; Seewaldt-Becker, E.; Weisenberger, H. Design of Highly Potent Nonpeptidic Fibrinogen Receptor Antagonists. Eur. J. Med. Chem. 1995, 30 (Suppl), 243s-254s. (d) Narjes, H.; Weisenberger, H.; Mueller, T. H.; Deichsel, G.; Krause, J. Tolerability and Platelet Fibrinogen Receptor Occupancy (FRO) After Oral Treatment with BIBU 104 XX in Healthy Volunteers. Thromb. Haemostasis 1995, 73, 1315. (e) Jones, C. R.; Ambros, R. J.; Rapold, H. J.; Steiner, B.; Weller, T.; van Heiningen, P. A Novel Non Peptide GPIIb-IIIa Antagonist in Man. Thromb. Haemostasis 1993, 69, 560-565. (f) Eldred, C. D.; Evans, B.; Hindley, S.; Judkins, B. D.; Kelly, H. A.; Kitchin, J.; Lumley, P.; 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-(Aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic Acid as Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885. (g) 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. (h) 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. S.; Miller, W. H.; Newlander, K. A.; Nichols, A. J.; 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.
22. During the course of this work a number of potent and selective GPIIb-IIIa receptor antagonists were described using benzamidine as an arginine surrogate. (a) Zablocki, J. A.; Miyano, M.; Garland, R. B.; Pireh, D.; Schretzman, L. A.; Rao, S. N.; Lindmark, R. J.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interaction. J. Med. Chem. 1995, 38, 2378-2394. (b) Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B. B.; Szalony, J. A.; Haas, N. F.; King, L. K.; Zablocki, J. A.; Keller, B. T.; Broschat, K.; Engleman, V. W.; Herin, M.; Jacqmin, P.; Feigen, L. P. SC-54684A: An Orally Active Inhibitor of Platelet Aggregation. Circulation, 1995 91, 403-410. (c) Himmelsbach, F.; Austel, V.; Guth, B.; Linz, G.; Muller, T. H.; Piper, H.; Seewaldt-Becker, E.; Weisenberger, H. Design of Highly Potent Nonpeptidic Fibrinogen Receptor Antagonists. Eur. J. Med. Chem. 1995, 30 (Suppl), 243s-254s. (d) Narjes, H.; Weisenberger, H.; Mueller, T. H.; Deichsel, G.; Krause, J. Tolerability and Platelet Fibrinogen Receptor Occupancy (FRO) After Oral Treatment with BIBU 104 XX in Healthy Volunteers. Thromb. Haemostasis 1995, 73, 1315. (e) Jones, C. R.; Ambros, R. J.; Rapold, H. J.; Steiner, B.; Weller, T.; van Heiningen, P. A Novel Non Peptide GPIIb-IIIa Antagonist in Man. Thromb. Haemostasis 1993, 69, 560-565. (f) Eldred, C. D.; Evans, B.; Hindley, S.; Judkins, B. D.; Kelly, H. A.; Kitchin, J.; Lumley, P.; 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-(Aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic Acid as Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885. (g) 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. (h) 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. S.; Miller, W. H.; Newlander, K. A.; Nichols, A. J.; 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.
23. During the course of this work a number of potent and selective GPIIb-IIIa receptor antagonists were described using benzamidine as an arginine surrogate. (a) Zablocki, J. A.; Miyano, M.; Garland, R. B.; Pireh, D.; Schretzman, L. A.; Rao, S. N.; Lindmark, R. J.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interaction. J. Med. Chem. 1995, 38, 2378-2394. (b) Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B. B.; Szalony, J. A.; Haas, N. F.; King, L. K.; Zablocki, J. A.; Keller, B. T.; Broschat, K.; Engleman, V. W.; Herin, M.; Jacqmin, P.; Feigen, L. P. SC-54684A: An Orally Active Inhibitor of Platelet Aggregation. Circulation, 1995 91, 403-410. (c) Himmelsbach, F.; Austel, V.; Guth, B.; Linz, G.; Muller, T. H.; Piper, H.; Seewaldt-Becker, E.; Weisenberger, H. Design of Highly Potent Nonpeptidic Fibrinogen Receptor Antagonists. Eur. J. Med. Chem. 1995, 30 (Suppl), 243s-254s. (d) Narjes, H.; Weisenberger, H.; Mueller, T. H.; Deichsel, G.; Krause, J. Tolerability and Platelet Fibrinogen Receptor Occupancy (FRO) After Oral Treatment with BIBU 104 XX in Healthy Volunteers. Thromb. Haemostasis 1995, 73, 1315. (e) Jones, C. R.; Ambros, R. J.; Rapold, H. J.; Steiner, B.; Weller, T.; van Heiningen, P. A Novel Non Peptide GPIIb-IIIa Antagonist in Man. Thromb. Haemostasis 1993, 69, 560-565. (f) Eldred, C. D.; Evans, B.; Hindley, S.; Judkins, B. D.; Kelly, H. A.; Kitchin, J.; Lumley, P.; 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-(Aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic Acid as Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885. (g) 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. (h) 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. S.; Miller, W. H.; Newlander, K. A.; Nichols, A. J.; 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.
24. During the course of this work a number of potent and selective GPIIb-IIIa receptor antagonists were described using benzamidine as an arginine surrogate. (a) Zablocki, J. A.; Miyano, M.; Garland, R. B.; Pireh, D.; Schretzman, L. A.; Rao, S. N.; Lindmark, R. J.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interaction. J. Med. Chem. 1995, 38, 2378-2394. (b) Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B. B.; Szalony, J. A.; Haas, N. F.; King, L. K.; Zablocki, J. A.; Keller, B. T.; Broschat, K.; Engleman, V. W.; Herin, M.; Jacqmin, P.; Feigen, L. P. SC-54684A: An Orally Active Inhibitor of Platelet Aggregation. Circulation, 1995 91, 403-410. (c) Himmelsbach, F.; Austel, V.; Guth, B.; Linz, G.; Muller, T. H.; Piper, H.; Seewaldt-Becker, E.; Weisenberger, H. Design of Highly Potent Nonpeptidic Fibrinogen Receptor Antagonists. Eur. J. Med. Chem. 1995, 30 (Suppl), 243s-254s. (d) Narjes, H.; Weisenberger, H.; Mueller, T. H.; Deichsel, G.; Krause, J. Tolerability and Platelet Fibrinogen Receptor Occupancy (FRO) After Oral Treatment with BIBU 104 XX in Healthy Volunteers. Thromb. Haemostasis 1995, 73, 1315. (e) Jones, C. R.; Ambros, R. J.; Rapold, H. J.; Steiner, B.; Weller, T.; van Heiningen, P. A Novel Non Peptide GPIIb-IIIa Antagonist in Man. Thromb. Haemostasis 1993, 69, 560-565. (f) Eldred, C. D.; Evans, B.; Hindley, S.; Judkins, B. D.; Kelly, H. A.; Kitchin, J.; Lumley, P.; 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-(Aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic Acid as Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885. (g) 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. (h) 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. S.; Miller, W. H.; Newlander, K. A.; Nichols, A. J.; 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.
25. During the course of this work a number of potent and selective GPIIb-IIIa receptor antagonists were described using benzamidine as an arginine surrogate. (a) Zablocki, J. A.; Miyano, M.; Garland, R. B.; Pireh, D.; Schretzman, L. A.; Rao, S. N.; Lindmark, R. J.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interaction. J. Med. Chem. 1995, 38, 2378-2394. (b) Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B. B.; Szalony, J. A.; Haas, N. F.; King, L. K.; Zablocki, J. A.; Keller, B. T.; Broschat, K.; Engleman, V. W.; Herin, M.; Jacqmin, P.; Feigen, L. P. SC-54684A: An Orally Active Inhibitor of Platelet Aggregation. Circulation, 1995 91, 403-410. (c) Himmelsbach, F.; Austel, V.; Guth, B.; Linz, G.; Muller, T. H.; Piper, H.; Seewaldt-Becker, E.; Weisenberger, H. Design of Highly Potent Nonpeptidic Fibrinogen Receptor Antagonists. Eur. J. Med. Chem. 1995, 30 (Suppl), 243s-254s. (d) Narjes, H.; Weisenberger, H.; Mueller, T. H.; Deichsel, G.; Krause, J. Tolerability and Platelet Fibrinogen Receptor Occupancy (FRO) After Oral Treatment with BIBU 104 XX in Healthy Volunteers. Thromb. Haemostasis 1995, 73, 1315. (e) Jones, C. R.; Ambros, R. J.; Rapold, H. J.; Steiner, B.; Weller, T.; van Heiningen, P. A Novel Non Peptide GPIIb-IIIa Antagonist in Man. Thromb. Haemostasis 1993, 69, 560-565. (f) Eldred, C. D.; Evans, B.; Hindley, S.; Judkins, B. D.; Kelly, H. A.; Kitchin, J.; Lumley, P.; 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-(Aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic Acid as Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885. (g) 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. (h) 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. S.; Miller, W. H.; Newlander, K. A.; Nichols, A. J.; 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.
26. During the course of this work a number of potent and selective GPIIb-IIIa receptor antagonists were described using benzamidine as an arginine surrogate. (a) Zablocki, J. A.; Miyano, M.; Garland, R. B.; Pireh, D.; Schretzman, L. A.; Rao, S. N.; Lindmark, R. J.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interaction. J. Med. Chem. 1995, 38, 2378-2394. (b) Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B. B.; Szalony, J. A.; Haas, N. F.; King, L. K.; Zablocki, J. A.; Keller, B. T.; Broschat, K.; Engleman, V. W.; Herin, M.; Jacqmin, P.; Feigen, L. P. SC-54684A: An Orally Active Inhibitor of Platelet Aggregation. Circulation, 1995 91, 403-410. (c) Himmelsbach, F.; Austel, V.; Guth, B.; Linz, G.; Muller, T. H.; Piper, H.; Seewaldt-Becker, E.; Weisenberger, H. Design of Highly Potent Nonpeptidic Fibrinogen Receptor Antagonists. Eur. J. Med. Chem. 1995, 30 (Suppl), 243s-254s. (d) Narjes, H.; Weisenberger, H.; Mueller, T. H.; Deichsel, G.; Krause, J. Tolerability and Platelet Fibrinogen Receptor Occupancy (FRO) After Oral Treatment with BIBU 104 XX in Healthy Volunteers. Thromb. Haemostasis 1995, 73, 1315. (e) Jones, C. R.; Ambros, R. J.; Rapold, H. J.; Steiner, B.; Weller, T.; van Heiningen, P. A Novel Non Peptide GPIIb-IIIa Antagonist in Man. Thromb. Haemostasis 1993, 69, 560-565. (f) Eldred, C. D.; Evans, B.; Hindley, S.; Judkins, B. D.; Kelly, H. A.; Kitchin, J.; Lumley, P.; 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-(Aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic Acid as Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885. (g) 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. (h) 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. S.; Miller, W. H.; Newlander, K. A.; Nichols, A. J.; 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. During the course of this work a number of potent and selective GPIIb-IIIa receptor antagonists were described using benzamidine as an arginine surrogate. (a) Zablocki, J. A.; Miyano, M.; Garland, R. B.; Pireh, D.; Schretzman, L. A.; Rao, S. N.; Lindmark, R. J.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interaction. J. Med. Chem. 1995, 38, 2378-2394. (b) Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B. B.; Szalony, J. A.; Haas, N. F.; King, L. K.; Zablocki, J. A.; Keller, B. T.; Broschat, K.; Engleman, V. W.; Herin, M.; Jacqmin, P.; Feigen, L. P. SC-54684A: An Orally Active Inhibitor of Platelet Aggregation. Circulation, 1995 91, 403-410. (c) Himmelsbach, F.; Austel, V.; Guth, B.; Linz, G.; Muller, T. H.; Piper, H.; Seewaldt-Becker, E.; Weisenberger, H. Design of Highly Potent Nonpeptidic Fibrinogen Receptor Antagonists. Eur. J. Med. Chem. 1995, 30 (Suppl), 243s-254s. (d) Narjes, H.; Weisenberger, H.; Mueller, T. H.; Deichsel, G.; Krause, J. Tolerability and Platelet Fibrinogen Receptor Occupancy (FRO) After Oral Treatment with BIBU 104 XX in Healthy Volunteers. Thromb. Haemostasis 1995, 73, 1315. (e) Jones, C. R.; Ambros, R. J.; Rapold, H. J.; Steiner, B.; Weller, T.; van Heiningen, P. A Novel Non Peptide GPIIb-IIIa Antagonist in Man. Thromb. Haemostasis 1993, 69, 560-565. (f) Eldred, C. D.; Evans, B.; Hindley, S.; Judkins, B. D.; Kelly, H. A.; Kitchin, J.; Lumley, P.; 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-(Aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic Acid as Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885. (g) 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. (h) 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. S.; Miller, W. H.; Newlander, K. A.; Nichols, A. J.; 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.
28. During the course of this work a number of potent and selective GPIIb-IIIa receptor antagonists were described using benzamidine as an arginine surrogate. (a) Zablocki, J. A.; Miyano, M.; Garland, R. B.; Pireh, D.; Schretzman, L. A.; Rao, S. N.; Lindmark, R. J.; Panzer-Knodle, S. G.; Nicholson, N. S.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. A Proposal on the Nature of the Binding Interaction. J. Med. Chem. 1995, 38, 2378-2394. (b) Nicholson, N. S.; Panzer-Knodle, S. G.; Salyers, A. K.; Taite, B. B.; Szalony, J. A.; Haas, N. F.; King, L. K.; Zablocki, J. A.; Keller, B. T.; Broschat, K.; Engleman, V. W.; Herin, M.; Jacqmin, P.; Feigen, L. P. SC-54684A: An Orally Active Inhibitor of Platelet Aggregation. Circulation, 1995 91, 403-410. (c) Himmelsbach, F.; Austel, V.; Guth, B.; Linz, G.; Muller, T. H.; Piper, H.; Seewaldt-Becker, E.; Weisenberger, H. Design of Highly Potent Nonpeptidic Fibrinogen Receptor Antagonists. Eur. J. Med. Chem. 1995, 30 (Suppl), 243s-254s. (d) Narjes, H.; Weisenberger, H.; Mueller, T. H.; Deichsel, G.; Krause, J. Tolerability and Platelet Fibrinogen Receptor Occupancy (FRO) After Oral Treatment with BIBU 104 XX in Healthy Volunteers. Thromb. Haemostasis 1995, 73, 1315. (e) Jones, C. R.; Ambros, R. J.; Rapold, H. J.; Steiner, B.; Weller, T.; van Heiningen, P. A Novel Non Peptide GPIIb-IIIa Antagonist in Man. Thromb. Haemostasis 1993, 69, 560-565. (f) Eldred, C. D.; Evans, B.; Hindley, S.; Judkins, B. D.; Kelly, H. A.; Kitchin, J.; Lumley, P.; 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-(Aminoiminomethyl)phenyl]-1-piperazinyl]-1-piperidineacetic Acid as Long-Acting, Broad-Spectrum Antithrombotic Agent. J. Med. Chem. 1994, 37, 3882-3885. (g) 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. (h) 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. S.; Miller, W. H.; Newlander, K. A.; Nichols, A. J.; 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.
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56. Low-energy conformations of the N-H and N-Me derivatives (7c,e) were generated using the software package QUANTA, version 4.1.1 (Molecular Simulations, Inc., San Diego, CA) using a SGI Indigo R4000 workstation.
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