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

Journal of Medicinal Chemistry

Volumn 39, Issue 23, 1996, Pages 4583-4591

  Hutchinson, John H ^a,b   Cook, Jacquelynn J ^a,b   Brashear, Karen M ^a,b   Breslin, Michael J ^a,b   Glass, Joan D ^a,b   Gould, Robert J ^a,b   Halczenko, Wasyl ^a,b   Holahan, Marie A ^a,b   Lynch, Robert J ^a,b   Sitko, Gary R ^a,b   Stranieri, Maria T ^a,b   Hartman, George D ^a,b  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Department of Medicinal Chemistry ^*

Author keywords

[No Author keywords available]

Indexed keywords

3 ETHYNYL N [[1,2,3,4 TETRAHYDRO 1 OXO 7 (1 PIPERAZINYL) 2 ISOQUINOLINYL]ACETYL] BETA ALANINE; 3 ETHYNYL N [[1,2,3,4 TETRAHYDRO 1 OXO 7 (1 PIPERAZINYL) 2 ISOQUINOLINYL]ACETYL] BETA ALANINE ETHYL ESTER; [[3 [2 (PIPERIDIN 4 YL)ETHYL] 2 OXOPIPERIDINYL]ACETYL] 3 METHYL BETA ALANINE; FIBRINOGEN RECEPTOR; FIBRINOGEN RECEPTOR ANTAGONIST; L 734217; N [[7 (PIPERAZIN 1 YL) 3,4 DIHYDRO 1(1H) OXOISOQUINOLIN 2 YL]ACETYL] 3 ETHYNYL BETA ALANINE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CONTROLLED STUDY; DOG; DRUG DESIGN; FEMALE; HUMAN; HUMAN CELL; LIPID SOLUBILITY; MALE; MONKEY; NONHUMAN; ORAL DRUG ADMINISTRATION; STRUCTURE ACTIVITY RELATION; THROMBOCYTE AGGREGATION; THROMBOCYTE AGGREGATION INHIBITION;

ANIMALS; DOGS; DRUG DESIGN; EVALUATION STUDIES; FEMALE; HUMANS; ISOQUINOLINES; MACACA MULATTA; MAGNETIC RESONANCE SPECTROSCOPY; MALE; PLATELET AGGREGATION INHIBITORS; PLATELET GLYCOPROTEIN GPIIB-IIIA COMPLEX; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 10544253079     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9604787     Document Type: Article

References (34)

1. Colman, R. W.; Marder, V. J.; Salzman, E. W.; Hirsch, J. Hemostasis and Thrombosis: Basic Principles and Clinical Practices; Lippincott Publishers: Philadelphia, PA, 1994.
2. Fitzgerald, D. J.; Roy, L.; Catella, F.; Fitzgerald, G. A. Platelet Activation in Unstable Coronory Disease. N. Engl. J. Med. 1986, 315, 983-989.
3. Schror, K. Antiplatelet Drugs a Comparative Review. Drugs 1995, 50 (1), 7-28.
4. Lefkovits, J.; Plow, E. F.; Topol, E. J. Platelet Glycoprotein IIb/IIIa Receptors in Cardiovascular Medicine. N. Engl. J Med. 1995, 332, 1553-1559.
5. Robinson, C. Abciximab. Drugs Future 1995, 20, 457-463.
6. The EPIC Investigators. Use of a Monoclonal Antibody Directed Against the Platelet Glycoprotein IIb/IIIa Receptor in High-Risk Coronary Angioplasty. N. Engl. J. Med. 1994, 330, 956.
7. Raddatz, P.; Gante, J. Recent Developments in Gylcoprotein IIb/IIIa Antagonists. Expert Opin. Ther. Pat. 1995, 5 (11), 1163-1183.
8. Ojima, I.; Chakravarty, S.; Dong, Q. Antithrombotic Agents: From RGD to Peptide Mimetics, Bioorg. Med. Chem. 1995, 3 337-360.
9. (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.; Chang, 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.
10. (b) Peerlinck, K.; De Lepeleire, I.; Goldberg, M.; Farrell, D.; Barrett, J.; Hand, E.; Panebianco, D.; Deckmyn, H.; Vermylen, J.; Arnout, J. MK-383 (L-700,462), a Selective Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Is Active in Man. Circulation 1993, 88 (1), 1512-1517.
11. 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.
12. Zablocki, J. A.; Rico, J. G.; Garland, R. B.; Rogers, T. E.; Williams, K.; Schretzman, L. A.; Shashidhar, A. R.; 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.; Jacqmin, P.; Nicholson, N. S.; Panzer-Knodle, S. G.; Haas, N. F.; Page, J. D.; Szalony, J. A.; 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 Baaed 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.
13. 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.
14. (a) Xue, C.-B.; Wityak, J.; Sielecki, T. M.; Cain, G. A.; Liu, J.; Bostrom, L. L.; DiMeo, S. V.; Higley, C. A.; Lalka, G. K.; Tobin, A. E.; Frietze, W. E.; Emmett, G.; Mousa, S. A.; Sze, J. Y.; Thoolen, M. J.; Reilly, T. M.; DeGrado, W. F.; Olsen, R. E.; Wexler, R. R. Synthesis and Pharmacology of Orally Active, Isoxazoline Glycoprotein IIb-IIIa Receptor Antagonists. 211th ACS Meeting, March 1996; Med132 (abstr).
15. (b) Zhang, L.-h.; Anzalone, L.; Ma, P.; Kauffman, G. S.; Storace, L.; Ward, R. The Chiral Specific Synthesis of DMP 754, a Platelet GP IIb/IIIa Antagonist. Tetrahedron Lett. 1996, 37, 4455-4458.
16. (a) Weller, T.; Alig, L.; Beresini, M.; Blackburn, B.; Bunting, S.; Hadvary, P.; Muller, M. H.; Knopp, D.; Levet-Trafit, B.; Lipari, M. T.; Modi, N. B.; Muller, M.; Refino, C. J.; Schmitt, M.; Schonholzer, P.; Weiss, S.; Steiner, B. Orally Active Fibrinogen Receptor Antagonists. 2. Amidoximes as Prodrugs of Amidines. J. Med. Chem. 1996, 39, 3139-3147.
17. (b) Theroux, P.; Kouz, S.; Knudtsor, M. L.; Kells, C.; Nasmith, J.; Roy, L.; Ave, S. D.; Steiner, B.; Xiao, Z.; Rapold, H. J. A Randomized Double-Blind Controlled Trial With the Non-Peptidic Platelet GPIIb/IIIa Antagonist Ro 44-9883 in Unstable Angina. Circulation 1994, 90, I-232 (abstr).
18. Himmelsbach, F.; Austel, V.; Guth, B.; Linz, G.; Muller, T. H.; Pieper, H.; Seewaldt-Becker, E.; Weisenberger, H. Design of Highly Potent Nonpeptidic Fibrinogen Receptor Antagonists. Eur. J. Med. Chem. 1995, 30, 243s-254s.
19. Miller, W. H.; Ku, T. W.; Ali, F. E.; Bondinell, W. E.; Calvo, R. R.; Davis, L. D.; Erhard, K. F.; Hall, L. B.; Huffman, W. F.; Keenan, R. M.; Kwon, C.; Newlander, K A.; Ross, S. T.; Samanen, J. M.; Takata, D. T.; Yuan, C.-K. Enantiospecific Synthesis of SB 214857, a potent, Orally Active, Nonpeptide Fibrinogen Receptor Antagonists. Tetrahedron Lett. 1995, 36, 9433-9436.
20. For the synthesis of β-alanines, see: (a) Cole, D. C. Recent Stereoselective Synthetic Approaches to β-Amino Acids. Tetrahedron 1994, 50, 9517-9582. (b) Juaristi, E.; Quintana, D.; Escalante, J. Enantioselective Synthesis of β-Amino Acids. Aldrichim. Acta 1994, 27, 3.
21. For the synthesis of β-alanines, see: (a) Cole, D. C. Recent Stereoselective Synthetic Approaches to β-Amino Acids. Tetrahedron 1994, 50, 9517-9582. (b) Juaristi, E.; Quintana, D.; Escalante, J. Enantioselective Synthesis of β-Amino Acids. Aldrichim. Acta 1994, 27, 3.
22. (a) Girard, Y.; Atkinson, J. G.; Belanger, P. C.; Fuentes, J. J.; Rokash, J.; Rooney, C. S.; Remy, D. C.; Hunt, C. A. Synthesis, Chemistry, and Photochemical Substitutions of 6,11-Dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-ones. J. Org. Chem. 1983, 48, 3220-3234.
23. (b) Samanen, J. Patent WO 94/29273, Dec. 22, 1994.
24. Specific β-alanines. (a) 3-Methyl, see ref 10. (b) 3-Ethynyl, see ref 11. (c) 3-Pyrid-3-yl, see Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P. R. A highly Stereoselective Michael Addition to an α,β-Unsaturated Ester as the Crucial Step in the Synthesis of a Novel β-Amino Acid-Containing Fibrinogen Receptor Antagonist. J. Org. Chem. 1993, 58, 7948-7951. (d) 2-Amino and 2-tosylamino, see Xue, C.-B.; Rafalski, M.; Roderick, J.; Eyermann, C. J.; Mousa, S.; Olsen, R. E.; DeGrado, W. F. Design and Synthesis and in Vitro Activities of a Series of Benzimidazole/Benzoxazole Glycoprotein IIb/IIIa Inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 339-344.
25. Specific β-alanines. (a) 3-Methyl, see ref 10. (b) 3-Ethynyl, see ref 11. (c) 3-Pyrid-3-yl, see Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P. R. A highly Stereoselective Michael Addition to an α,β-Unsaturated Ester as the Crucial Step in the Synthesis of a Novel β-Amino Acid-Containing Fibrinogen Receptor Antagonist. J. Org. Chem. 1993, 58, 7948-7951. (d) 2-Amino and 2-tosylamino, see Xue, C.-B.; Rafalski, M.; Roderick, J.; Eyermann, C. J.; Mousa, S.; Olsen, R. E.; DeGrado, W. F. Design and Synthesis and in Vitro Activities of a Series of Benzimidazole/Benzoxazole Glycoprotein IIb/IIIa Inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 339-344.
26. Specific β-alanines. (a) 3-Methyl, see ref 10. (b) 3-Ethynyl, see ref 11. (c) 3-Pyrid-3-yl, see Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P. R. A highly Stereoselective Michael Addition to an α,β-Unsaturated Ester as the Crucial Step in the Synthesis of a Novel β-Amino Acid-Containing Fibrinogen Receptor Antagonist. J. Org. Chem. 1993, 58, 7948-7951. (d) 2-Amino and 2-tosylamino, see Xue, C.-B.; Rafalski, M.; Roderick, J.; Eyermann, C. J.; Mousa, S.; Olsen, R. E.; DeGrado, W. F. Design and Synthesis and in Vitro Activities of a Series of Benzimidazole/Benzoxazole Glycoprotein IIb/IIIa Inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 339-344.
27. Specific β-alanines. (a) 3-Methyl, see ref 10. (b) 3-Ethynyl, see ref 11. (c) 3-Pyrid-3-yl, see Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P. R. A highly Stereoselective Michael Addition to an α,β-Unsaturated Ester as the Crucial Step in the Synthesis of a Novel β-Amino Acid-Containing Fibrinogen Receptor Antagonist. J. Org. Chem. 1993, 58, 7948-7951. (d) 2-Amino and 2-tosylamino, see Xue, C.-B.; Rafalski, M.; Roderick, J.; Eyermann, C. J.; Mousa, S.; Olsen, R. E.; DeGrado, W. F. Design and Synthesis and in Vitro Activities of a Series of Benzimidazole/Benzoxazole Glycoprotein IIb/IIIa Inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 339-344.
28. (a) Kirk, K. L. 4-Lithio-1-tritylimidazole as a Synthetic Intermediate. Synthesis of Imidazole-4-carboxaldehyde. J. Heterocycl. Chem. 1985, 22, 57-59.
29. (b) Iddon, B.; Lim, B. L. Metal-Halogen Exchange Reactions of Mono- and Polyhalogenimidazoles, J. Chem. Soc., Perkin Trans. 1 1983, 735-739.
30. Stokker, G. E. Preparation of 1,2,3,4-Tetrahydroisoquinolines Lacking Electron Donating Groups - An Intramolecular Cyclization Complementary to the Pictet-Spengler Reaction. Tetrahedron Lett. 1996, 37, 5453-5456.
31. a values of 11.2 and 8.7, respectively.
32. 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. Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-Asp. J. Med. Chem. 1994, 37, 2537-2551.
33. log P data were measured using 1-octanol/phosphate buffer, pH 7.4, system.
34. The intravenous and oral administration of these compounds to dogs and monkeys in the in vivo studies described did not result in any significant change in circulating whole blood platelet count.