C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 13, 1998, Pages 1719-1724

  Isaacs, Richard C A ^a   Cutrona, Kellie J ^a   Newton, Christina L ^a   Sanderson, Philip E J ^a   Solinsky, Mark G ^a   Baskin, Elizabeth P ^a   Chen, I Wu ^a   Cooper, Carolyn M ^a   Cook, Jacquelynn J ^a   Gardell, Stephen J ^a   Lewis, S Dale ^a   Lucas Jr , Robert J ^a   Lyle, Elizabeth A ^a   Lynch Jr , Joseph J ^a   Naylor Olsen, Adel M ^a   Stranieri, Maria T ^a   Vastag, Kari ^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; L 375052; PYRIDONE DERIVATIVE; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ANTICOAGULATION; ARTICLE; BLOOD CLOT LYSIS; CAT; DOG; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; INTRAVENOUS DRUG ADMINISTRATION; LIPOPHILICITY; NONHUMAN; ORAL DRUG ADMINISTRATION; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; ANTITHROMBINS; BIOLOGICAL AVAILABILITY; DOGS; PYRIDINES; PYRIDONES; RATS; SULFANILAMIDES; SULFONAMIDES;

EID: 0032493332     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00297-2     Document Type: Article

References (20)

1. 1. (a) Powers, J. C.; Kam, C. -M. In Thrombin: Structure and Function; Berliner, L., Ed.; Plenum: New York, 1992; pp 117-158.
2. (b) Claeson, G. Blood Coagulation Fibrinolysis 1994, 5, 411.
3. (c) Kimball, S. D. Blood Coagulation Fibrinolysis 1995, 6, 511.
4. 2. For recent reviews see (a) Ripka, W. C.; Vlasuk, G. P. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic: San Diego, 1997; Vol. 32, pp 71-89.
5. (b) Wiley, M. R.; Fisher, M. J. Exp. Opin. Ther. Patents 1997, 7, 1265.
6. 3. (a) Sanderson, P. E. J.; Dyer, D. L.; Naylor-Olsen, A. M.; Vacca, J. P.; Gardell, S. J.; Lewis, S. D.; Lucas, R. J.; Lyle, E. A.; Lynch, J. J.; Mulichak, A. M. Bioorg. Med. Chem. Lett. 1997, 7, 1497.
7. (b) Sanderson, P. E. J.; Cutrona, K. J.; Dorsey, B. D.; Dyer, D. L.; McDonough, C.; Naylor-Olsen, A. M.; Chen, I. -W.; Chen, Z.; Cook, J. J.; Gardell, S. J.; Krueger, J. A.; Lewis, S. D.; Lin, J. H.; Lucas, R. J.; Lyle, E. A.; Lynch, J. J.; Stranieri, M. T.; Vastag, K.; Shafer, J. A.; Vacca, J. P. Bioorg. Med. Chem. Lett. 1998, 8, 817.
8. 4. For the first report that the glycylproline amide backbone of covalent peptide inhibitors of human leukocyte elastase could be effectively replaced by a 3-amino-2-pyridinone template, see: Brown, F. J.; Andisik, D. W.; Bernstein, P. R.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R.; Edwards, P. D.; Earley, R. A.; Feeney, S.; Green, R. C.; Gomes, B.; Kosmider, B. J.; Krell, R. D.; Shaw, A.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Tuthill, P. A.; Warner, P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. J. Med. Chem. 1994, 37, 1259. For the application of this template to the design of covalent, arginine aldehyde derived thrombin inhibitors, see: Tamura, S. Y.; Semple, J. E.; Reiner, J. E.; Goldman, E. A.; Brunk, 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, 1534.
9. 4. For the first report that the glycylproline amide backbone of covalent peptide inhibitors of human leukocyte elastase could be effectively replaced by a 3-amino-2-pyridinone template, see: Brown, F. J.; Andisik, D. W.; Bernstein, P. R.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R.; Edwards, P. D.; Earley, R. A.; Feeney, S.; Green, R. C.; Gomes, B.; Kosmider, B. J.; Krell, R. D.; Shaw, A.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Tuthill, P. A.; Warner, P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. J. Med. Chem. 1994, 37, 1259. For the application of this template to the design of covalent, arginine aldehyde derived thrombin inhibitors, see: Tamura, S. Y.; Semple, J. E.; Reiner, J. E.; Goldman, E. A.; Brunk, 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, 1534.
10. 5. (a) Kurz, K. D.; Main, B. W.; Sandusky, G. E. Thromb. Res. 1990, 60, 269;
11. (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.; Cook, J. J.; Gardell, S. J.; Shafer, J. A. Thromb. Haemostasis 1995, 74, 1107. (equation presented)
12. 14 to give a mixture of the aldehyde and the corresponding acid. Jones oxidation completed the transformation. Finally, coupling and deprotection as described for 3 gave 4.
13. 7. The full results of SAR studies of the P3 ligand in our pyridinone derived thrombin inhibitors will be disclosed at a later date.
14. 8. For a thorough discussion of the interactive effects of potency, lipophilicity and protein binding on oral bioavailability and antithrombotic efficacy see Tucker, T. J.; Lumma, W. C.; Lewis, S. D.; Gardell, S. J.; Lucas, R. J.; Baskin, E. P.; Woltmann, R.; Lynch, J. J.; Lyle, E. A.; Appleby, S. D.; Chen, I. -W.; Dancheck, K. B.; Vacca, J. P. J. Med. Chem. 1997, 40, 1565.
15. 9. Hoffman, J. M.; Wai, J. S.; Thomas, C. M.; Levin, R. B.; O'Brien, J. A.; Goldman, M. E. J. Med. Chem. 1992, 35, 3784.
16. 10. Sanderson, P. E. J.; Dyer, D. L.; Naylor-Olsen, A. M.; Vacca, J. P.; Isaacs, R. C. A.; Dorsey, B. D.; Fraley, M. E. U.S. Patent 5,668,289.
17. 11. The reduction of the cyclopropyl group yielded only the n-propyl group. None of the iso-propyl isomer was ever observed.
18. 12. This flexibility of the S2 pocket has been observed in the crystal structure of a non-peptide series of thrombin inhibitors. See Naylor-Olsen, A. M.; Ponticello, G. S.; Lewis, S. D.; Mulichak, A. M.; Chen, Z.; Habecker, C. N.; Sanders, W. M.; Tucker, T. J.; Shafer, J. A.; Vacca, J. P. Bioorg. Med. Chem. Lett. 1998, 8, xxx.
19. 13. Lang, R. W.; Wenk, P. F. Helv. Chim. Acta 1988, 71, 596.
20. 14. Carlsen, P. H. J., Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936.