Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 5, 1999, Pages 759-764

  Takeuchi, Kumiko ^a   Kohn, Todd J ^a   Sall, Daniel J ^a   Denney, Michael L ^a   McCowan, Jefferson R ^a   Smith, Gerry F ^a   Gifford Moore, Donetta S ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZOTHIOPHENE DERIVATIVE; CYCLOHEXANE; DIBENZOTHIOPHENE DERIVATIVE; HYDROXYL GROUP; PIPERIDINE DERIVATIVE; THROMBIN INHIBITOR;

ARTICLE; DRUG CONFORMATION; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME INHIBITION; STRUCTURE ACTIVITY RELATION;

STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES; THROMBIN;

EID: 0033535387     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00076-1     Document Type: Article

References (12)

1. Machovich, R. In The Thrombin; Machovich, R., Ed.; CRC Press: Boca Raton, 1984; Vol 1, pp 1-22.
2. (a) Hirsh, J.; Salzman, E. W.; Marder, V. J.; Colman, R. W. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 2nd Ed.; Colman, R. W.; Hirsh, J.; Marder, V. J.; Salzman, E. W, Eds.; Lippincott: Philadelphia, 1987; pp 1063-1072.
3. (b) Hirsh, J.; Salzman, E. W. Ibid. Pp 1199-1207.
4. (c) Barnett, H. J. M. Ibid. Pp 1301-1315.
5. Sall, D. J.; Bastian, J. A.; Briggs, S. L.; Buben, J. A.; Chirgadze, N. Y.; Clawson, D. K.; Denney, M. L.; Gierra, D. D.; Gifford-Moore, D. S.; Harper, R. W.; Hauser, K. L.; Klimkowski, V. J.; Kohn, T. J.; Lin, H.- S.; McCowan, J. R.; Palkowitz, A. D.; Smith, G. F.; Takeuchi, K.; Thrasher, K. J.; Tinsley, J. M.; Utterback, B. G.; Yan, S.-C. B.; Zhang. M. J. Med. Chem. 1997, 40, 3489.
6. Ple, P. A.; Marnert, L. J. J. Heterocyclic Chem. 1988, 25, 1271. See also Graham, S. L.; Shepard, K. L.; Andersen, P. S.; Baldwin, J. J.; Best, D. B.; Christy, M. E.; Freedman, M. B.; Gautheron, P.; Habecker, C. N.; Hoffman, J. M.; Lyle, P. A.; Michelson, S. R.; Ponticello, G. S.; Robb, C. M.; Schwam, H.; Smith, A. M.; Smith, R. L.; Sondey, J. M.; Strohmaier, K. M.; Sugrue, M. F.; Varga, S. L. J. Med. Chem. 1989, 32, 2548.
7. Ple, P. A.; Marnert, L. J. J. Heterocyclic Chem. 1988, 25, 1271. See also Graham, S. L.; Shepard, K. L.; Andersen, P. S.; Baldwin, J. J.; Best, D. B.; Christy, M. E.; Freedman, M. B.; Gautheron, P.; Habecker, C. N.; Hoffman, J. M.; Lyle, P. A.; Michelson, S. R.; Ponticello, G. S.; Robb, C. M.; Schwam, H.; Smith, A. M.; Smith, R. L.; Sondey, J. M.; Strohmaier, K. M.; Sugrue, M. F.; Varga, S. L. J. Med. Chem. 1989, 32, 2548.
8. Aalten, H. L.; van Koten, G.; Grove, D. M.; Kuilman, T.; Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A. Tetrahedron 1989, 45, 5565.
9. Friedel-Crafts acylation of 4- and 7-methoxybenzo[b]thiophene derivatives took place at the para-position to the methoxy substituent, yielding 7- and 4-acylated products, respectively. Regioselective Friedel-Crafts acylation at the C3 position of the benzo[b]thiophenes was effected when the corresponding hydroxy derivatives of 7 were employed. This interesting regioselectivity in the Friedel-Crafts acylation of alkoxybenzo[b]thiophene derivatives will be reported elsewhere
10. Ablenas, F. J.; George, B. E.; Maleki, M.; Jain, R.; Hopkinson, A. C.; Lee-Ruff, E. Can. J. Chem. 1987, 65, 1800.
11. Grese, T, A.; Cho, S.; Finley, D. R.; Godfrey, A. G.; Jones, C. D.; Lugar III, C. W.; Martin, M. J.; Matsumoto, K.; Pennington, L. D.; Winter, M. A.; Adrian, M. D.; Cole, H. W.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Short, L. L.; Glasebrook, A. L.; Bryant, H. U. J. Med. Chem. 1997, 40, 146.
12. Experiments with the A-V shunt model were performed with slight modifications of the methods of Smith, J. R.; White, A. M. Br. J. Pharmacol. 1982, 77, 29. Drug or vehicle was infused for 15 min prior to opening the shunt and was continued for an additional 15 min after the shunt was opened. Net clot weights from drug-treated animals were expressed as a percent of the vehicle-treated animals run in the same experiment. Compound 27 significantly reduced the clot size at concentration of 66 μmole/kg/hr iv.