L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 7, 1998, Pages 817-822

  Sanderson, Philip E J ^a   Cutrona, Kellie J ^a   Dorsey, Bruce D ^a   Dyer, Dona L ^a   McDonough, Colleen M ^a   Naylor Olsen, Adel M ^a   Chen, I Wu ^a   Chen, Zhongguo ^a   Cook, Jacquelynn J ^a   Gardell, Stephen J ^a   Krueger, Julie A ^a   Lewis, S Dale ^a   Lin, Jiunn H ^a   Lucas Jr , Bobby J ^a   Lyle, Elizabeth A ^a   Lynch Jr , Joseph J ^a   Stranieri, Maria T ^a   Vastag, Kari ^a   Shafer, Jules A ^a   Vacca, Joseph P ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2 AMINO 6 METHYL 5 PYRIDINYLMETHYLAMINOCARBONYLMETHYL) 3 BENZYLSULFONAMIDO 6 METHYL 2 PYRIDINONE; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CHEMICAL MODIFICATION; DOG; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG STRUCTURE; DRUG SYNTHESIS; INTRAVENOUS DRUG ADMINISTRATION; MONKEY; NONHUMAN; ORAL DRUG ADMINISTRATION; THROMBOSIS; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; ANTICOAGULANTS; BIOLOGICAL AVAILABILITY; CRYSTALLOGRAPHY, X-RAY; DOGS; FERRIC COMPOUNDS; KINETICS; MACACA FASCICULARIS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PYRIDONES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; THROMBIN; THROMBOSIS; TRYPSIN;

ANIMALIA; CANIS FAMILIARIS; MACACA FASCICULARIS;

EID: 0032492658     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00117-6     Document Type: Article

References (24)

1. 1. (a) Stürzebecher, J.; Meier, J. J. Enzyme Inhibition 1995, 9, 1;
2. (b) Kimball, S. D. Blood Coagulation and Fibrinolysis 1995, 6, 511.
3. 2. (a) Cousins, G. R.; Friedrichs, G. S.; Sudo, Y.; Rebello, S. S.; Rote, W. E.; Vlasuk, G. P.; Nolan, T. G.; Mendoza, C.; Lucchesi, B. R. Circulation 1996, 94, 1705;
4. (b) Rebello, S. S.; Miller, B. V.; Basler, G. C.; Lucchesi, B. R. J. Cardiovasc. Pharmacol. 1997, 29, 240.
5. 3. Tamura, S. Y.; Semple, J. E.; Reiner, J. E.; Goldman, E. A.; Brunck, T. K.; Lim-Wilby, M. S.; Carpenter, S, H.; Rote, W. E. Oldeshulte, G. L.; Richard, B. M.; Nutt, R. F.; Ripka, W. C. Bioorg. Med. Chem. Lett. 1997, 7, 1543.
6. 4. (a) Brady, S. F.; Stauffer, K. J.; Smith, G. M.; Lewis, S. D.; Lucas, B. J.; Naylor-Olsen, A. M.; Ramjit, H.; Lumma, W. C. Abstract from the Second Winter Conference on Medicinal and Bioorganic Chemistry, Jan. 26-31, 1997, Steamboat Springs, Colorado
7. (b) Brady, S. F.; Stauffer, K. J.; Lumma, W, C.; Smith, G. M.; Ramjit, H.; Lewis, S. D.; Lucas, B. J.; Gardell, S. J.; Lyle, E. A.; Appleby, S. D.; Cook, J. J.; Holahan, M. A.; Stranieri, M. T.; Lynch, J. J.; Lin, J. H.; Chen, I-W.; Vastag, K.; Naylor-Olsen, A. M.; Vacca, J. P. J. Med. Chem. 1998, 41, 401.
8. 5. Tucker, T. J.; Lumma, W. C.; Lewis, S. D.; Gardell, S. J.; Lucas, B. J.; Baskin, E. P.; Woltmann, R.; Lynch, J. J.; Lyle, E. A.; Appleby, S. A.; Chen, I-W.; Dancheck, K. B.; Vacca, J. P. J. Med. Chem. 1997, 40, 1565.
9. 6. (a) Feng, D-M.; Freidinger, R. M.; Lewis, S. D.; Gardell, S. J.; Bock, M. G.; Chen, Z.; Naylor-Olsen, A. M.; Woltmann, R.; Baskin, E. P.; Lynch, J. J.; Lucas, B. J.; Shafer, J. A.; Dancheck, K. B.; Chen, I-W.; Vacca, J. P. In Peptides: Chemistry, Structure and Biology (Proceedings of the Fifteenth American Peptide Symposium); Tam, G. P. and Hodges, R. S., Eds.; Mayflower Scientific Ltd., England, 1997;
10. (b) Feng, D-M.; Gardell, S. J.; Lewis, S. D.; Bock, M. G.; Chen, Z.; Freidinger, R. M.; Naylor-Olsen, A. M.; Ramjit, H. G.; Woltmann, R.; Baskin, E. P.; Lynch, J. J.; Lucas, B. J.; Shafer, J. A.; Dancheck, K. B.; Chen, I-W.; Mao, S-S.; Krueger, J. A.; Hare, T. R.; Mulichak, A. M.; Vacca, J. P. J. Med. Chem. 1997, 40, 3726.
11. 7. Others have specifically claimed aminopyridines as thrombin inhibitors: Smith, G. F.; Wiley, M. R.; Schacht, A. L.; Shuman, R. T. Antithrombotic Agents. Int. Pat. Appl. WO 95/23609, 8, September, 1995.
12. 8. Sanderson, P. E. J.; Dyer, D. L.; Naylor-Olsen, A. M.; Vacca, J. P.; Gardell, S. J.; Lewis, S. D.; Lucas, B. J.; Lyle, E. A.; Lynch, J. J.; Mulichak, A. M. Bioorg. Med. Chem. Lett. 1997, 7, 1497.
13. 9. Tucker, T. J.; Lumma, W. C.; Naylor-Olsen, A. M.; Lewis, S. D.; Lucas, B. J.; Freidinger, R. M. J. Med. Chem. 1997, 40, 830.
14. 10. Dorsey, B. D.; McDonough, C. M. unpublished results.
15. 11. (a) Bode, W.; Turk, D.; Karshikov, A. J. Protein Sci. 1992, 86, 426;
16. (b) Chen, Z.; Li, Y.; Mulichak, A. M.; Lewis, S. D.; Shafer, J. A. Arch. Biochem. Biophys. 1995, 322, 198.
17. 12. For the synthesis and characterization of the compounds in Table 1 see: Sanderson, P. E. J.; Naylor-Olsen, A. M.; Dyer, D. L.; Vacca, J. P.; Isaacs, R. C.; Dorsey, B. D.; Fraley, M. E. Pyridinone-Thrombin Inhibitors. Int. Pat. Appl., WO 97/01338, 16 January, 1997.
18. 1 data quoted in this report are for the human enzymes.
19. 14. Lyle, T. A.; Chen, Z.; Appleby, S. D.; Freidinger, R. M.; Gardell, S. J.; Lewis, S. D.; Li, Y.; Lyle, E. A.; Lynch, J. J. Jr.; Mulichak, A. M.; Ng, A. S.; Naylor-Olsen, A. M.; Sanders, W. M. Bioorg. Med. Chem. Lett. 1997, 7, 67.
20. 15. The crystal structures of related P3-P4 lactam benzylsulfonamides have been reported: (a) Levy, O. E.; Semple, J. E.; Lim, M. L.; Reiner, J.; Rote, W. E.; Dempsey, E.; Richard, B. M.; Zhang, Erli.; Tulinsky, A.; Ripka, W. C.; Nutt, R. F. J. Med. Chem. 1996, 39, 4527;
21. (b) Semple, J. E.; Rowley, D. C.; Brunck, T. K.; Ha-Uong, T.; Minami, N. K., Owens, T. D.; Tamura, S. Y.; Goldman, E. A.; Siev, D. V.; Ardecky, R. J.; Carpenter, S. H.; Ge, Y.; Richard, B. M.; Nolan, T. G.; Håkanson, K.; Tulinsky. A.; Nutt, R. F.; Ripka, W. C. J. Med. Chem. 1996, 39, 4531.
22. 16. For the nomenclature see: Hilpert, K.; Ackermann, J.; Banner, D. W.; Gast, A.; Gubernator, K.; Hadvary, P.; Labler, L.; Muller, K.; Schmid, G.; Tschopp, T. B.; van de Waterbeemd, H. J. Med. Chem. 1994, 37, 3889.
23. 17. (a) Kurz, K. D.; Main, B. W.; Sandusky, G. E. Thromb. Res., 1990, 60, 269
24. (b) Lewis, S. D.; Ng, A. S.; Lyle, E. A.; Mellott, M. J.; Appleby, S. D.; Brady, S. F.; Stauffer, K. J. Sisko, J. T.; Mao, S-S.: Veber, D. F.; Nutt, R. F.; Lynch, J. J. Jr.; Cook, J. J.; Gardell, S. J.; Shafer, J. A. Thromb. Haemostasis, 1995, 74, 1107.