Synthesis, SAR and in vivo activity of novel thienopyridine sulfonamide pyrrolidinones as factor Xa inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 18, 1999, Pages 2753-2758

  Becker, Michael R ^a   Ewing, William R ^a   Davis, Roderick S ^a   Pauls, Henry W ^a   Ly, Cuong ^a   Li, Aiwen ^a   Mason, Helen J ^a   Choi Sledeski, Yong Mi ^a   Spada, Alfred P ^a   Chu, Valeria ^a   Brown, Karen D ^a   Colussi, Dennis J ^a   Leadley, Robert J ^a   Bentley, Ross ^a   Bostwick, Jeff ^a   Kasiewski, Charles ^a   Morgan, Suzanne ^a  

^a Rhône Poulenc Rorer ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 PYRROLIDONE DERIVATIVE; BLOOD CLOTTING FACTOR 10A; FUNCTIONAL GROUP; ISOQUINOLINE DERIVATIVE; QUINOLINE DERIVATIVE;

ARTICLE; CHEMICAL MODIFICATION; DRUG BINDING; DRUG SYNTHESIS; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

ANIMALS; DOGS; FACTOR XA; PYRROLIDINONES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBOSIS;

EID: 0033588944     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00466-7     Document Type: Article

References (30)

1. 1. (a) Ewing, W. R.; Pauls, H. W.; Spada, A. P. Drugs of the Future, in press,
2. (b) Sanderson, P. E. J. Med. Res. Rev. 1999, 19, 179.
3. (c) Al-Obeidi, F.; Ostrem, J. Drug Discovery Today 1998, 3, 223.
4. (d) Vacca, J. P. Annu. Rep. Med. Chem. 1998, 33, 81.
5. 2. Esmon, C. T. Annu. Rev. Cell Biol. 1993, 9, 1.
6. 3. Ewing, W. R.; Becker, M. R.; Manetta, V. E.; Davis, R. S.; Pauls, H. W.; Mason, H.; Choi-Sledeski, Y. M.; Green, D.; Cha, D.; Spada, A.; Cheney, D. L.; Mason, J. S.; Brown, K.; Colussi, D.; Bentley, R.; Bostwick, J.; Kasiewski, C. J.; Morgan, S. R.; Leadley, R. J.; Maignon, S.; Guilloteau, J.-P.; Dunwiddie, C. T.; Perrone, M. H.; Chu, V. J. Med. Chem., in press.
7. 4. Choi-Sledeski, Y. M.; McGarry, D. G.; Green, D. M.; Mason, H. J.; Becker, M. R.; Davis, R. S.; Ewing, W. R.; Dankulich, W. P.; Manetta, V. E.; Morris, R. L.; Spada, A.; Cheney, D.; Brown, K. D.; Colussi, D. J.; Chu, V.; Heran, C. L.; Morgan, S. R.; Bentley, R.; Leadley, R.; Maignon, S.; Guilloteau, J.-P.; Dunwiddie, C. T.; Pauls, H. J. Med. Chem., in press.
8. 5. (a) Brandstetter, H.; Kuhne, A.; Bode, W.; Huber, R.; von der Saal, W.; Wirthensohn, K.; Engh, R. A. J. Biol. Chem. 1996, 271, 29988.
9. (b) Tulinsky, A.; Padmanbhan, K.; Padmanbhan, K. P.; Park, C. H.; Bode, W.; Huber, R.; Blankenship, D. T.; Cardin, A. D.; Kiesel, W. J. Mol. Biol. 1993, 232, 947.
10. 6. Choi-Sledeski, Y. M.; Pauls, H. W.; Becker, M. R.; Ewing, W. R.; Green, D. M.; Ly, C.; Davis, R.; Morton, G.; Mason, H. J.; Gong, Y.; Gardner, C.; Jiang, J. Z.; Li, A.; Spada, A.; Barton, J.; Liang, G.; Chu, V.; Brown, K.; Colussi, D.; Bentley, R.; Leadley, R.; Dunwiddie, C.; Maignan, S.; Guilloteau, J.-P. Book of Abstracts, 217th ACS National Meeting, Anaheim, CA, March 21-25 1999; American Chemical Society: Washington, D.C., 1999; MEDI-080.
11. 7. (a) Weber, A.-A.; Schroer, K. Haemostasologie (Stgt.) 1998, 18, 180.
12. (b) Schroer, K. Drugs 1995, 50, 7.
13. 8. El-Abadelah, M. M.; Nazer, M. Z.; Okasha, S. F.; Calas, M.; Bompart, J.; Mion, P. Eur. J. Med. Chem. 1998, 33, 33.
14. 9. (a) Klemm, L. H. Trends Heterocycl. Chem. 1997, 5, 37.
15. (b) Walker, M. P.; Moberg, W. K. Book of Abstracts, 214th ACS National Meeting, Las Vegas, NV, September 7-11, 1997; American Chemical Society: Washington, D.C., 1997; ORGN-174.
16. i's were determined from triplicate runs.
17. 11. All final compounds were purified by preparative reverse phase HPLC using a solvent gradient of 10-40% to 70-100% acetonitrile/0.1% TFA water, lyophilized and isolated as their TFA salts.
18. 12. Nuvole, A.; Pinna, G. A. J. Heterocycl. Chem. 1978, 15, 1513.
19. 13. Luo, J.-K.; Castle, S. L.; Castle, R. N. J. Heterocycl. Chem. 1990, 27, 2047 and references cited therein.
20. 14. (a) Warner, P.; Barker, A. J.; Jackman, A. L.; Burrows, K. D.; Roberts, N.; Bishop, J. A. M.; O'Connor, B. M.; Hughes, L. R. J. Med. Chem. 1992, 35, 2761.
21. (b) Manimaran, T.; Thiruvengadam, T. K.; Ramakrishnan, V. T. Synthesis 1975, 739.
22. (c) Eloy, F.; Deryckere, A. Helv. Chim. Acta 1970, 3, 645.
23. 15. Hamada, T.; Yonemitsu, O. Synthesis 1986, 852.
24. 16. (a) Meth-Cohn, O.; Narine, B.; Taranowski, B. J. Chem. Soc., Perkin I 1981, 1531.
25. (b) Meth-Cohn, O.; Narine, B. Tetrahedron Lett. 1978, 23, 2045.
26. 17. Klemm, L. H.; Louris, J. N. J. Heterocycl. Chem. 1984, 21, 785.
27. 18. Results to be published separately.
28. 19. Kurz, K. D.; Main, B. W.; Sandusky, G. E. Thromb. Res. 1990, 60, 269.
29. 20. Efficacy is defined by a ≥ 50% reduction in thrombus mass (TM) from saline control and a ≥ 100% increase in time to occlusion (TTO) from control.
30. 21. Rebello, S. S.; Miller, B. V.; Basler, G. C.; Lucchesi, B. R. J. Cardiovasc. Pharmacol. 1997, 2, 240.