Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 2. Sidechain optimization and demonstration of in vivo efficacy

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 5, 1999, Pages 775-780

  Zhang, Minsheng ^a,b   Bailey, Dianna L ^a   Bastian, Jolie A ^a   Briggs, Stephen L ^a   Chirgadze, Nickolay Y ^a   Clawson, David K ^a   Denney, Michael L ^a   Gifford Moore, Donetta S ^a   Harper, Richard W ^a   Johnson, Lea M ^a   Klimkowski, Valentine J ^a   Kohn, Todd J ^a   Lin, Ho Shen ^a   McCowan, Jefferson R ^a   Richett, Michael E ^a   Sall, Daniel J ^a   Smith, Amy J ^a   Smith, Gerald F ^a   Snyder, David W ^a   Takeuchi, Kumiko ^a   Utterback, Barbara G ^a   Yan, Sau Chi B ^a   more..

^a ELI LILLY AND COMPANY   (United States)

^b BRISTOL MYERS SQUIBB PHARMACEUTICAL RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZOTHIOPHENE DERIVATIVE; EFEGATRAN; THROMBIN INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTICOAGULANT THERAPY; ANTICOAGULATION; ARTICLE; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; DRUG BINDING SITE; DRUG CONFORMATION; ELECTRICITY; HYDROPHOBICITY; IN VIVO STUDY; NONHUMAN; ORAL DRUG ADMINISTRATION; PARTIAL THROMBOPLASTIN TIME; PLASMA; PROTHROMBIN TIME; RAT; STRUCTURE ACTIVITY RELATION; THROMBIN TIME; X RAY CRYSTALLOGRAPHY;

ANIMALS; ANTICOAGULANTS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DISEASE MODELS, ANIMAL; HUMANS; MODELS, MOLECULAR; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES; THROMBIN; THROMBOSIS;

ANIMALIA;

EID: 0033535402     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00074-8     Document Type: Article

References (27)

1. For recent reviews: (a) Scarborough, R. M. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic: San Diego, 1995; Vol. 30, pp 71-80.
2. (b) Kimball, S. D. Curr. Pharm. Des. 1995, 1, 441.
3. (c) Tapparelli, C.; Metternich, R.; Ehrhardt, C.; Cook, N. S. Trends Pharmacol. Sci. 1993, 14, 366.
4. (d) Lefkovits, J.; Topol, E. J. Circulation 1994, 90, 1522.
5. (e) Ofosu, F. A.; Agnelli, G.; Hirsh, J. Recent Adv. Haematol. 1992, 6, 45.
6. For most recent reports: (a) Tucker, T. J.; Lumma, W. C.; Mulichak, A. M; Chen, Z.; Naylor-Olsen, A. M.; Lewis, S. D.; Lucas, R.; Freidinger, R. M.; Kuo, L. C. J. Med. Chem. 1997, 40, 830.
7. (b) Levy, O. E.; Semple, J. E.; Lim, M. L.; Reiner, J.; Rote, W. E.; Dempsey, E.; Richard, B. M.; Zhang, E.; Tulinsky, A.; Ripka, W. C.; Nutt, R. F. J. Med. Chem. 1996, 39, 4527.
8. (c) 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.; Hakanson, K.; Tulinsky, A.; Nutt, R. F.; Ripka, W. C. J. Med. Chem. 1996, 39, 4531.
9. (d) Tamura, S. Y.; Goldman, E. A.; Brunck, T. K.; Ripka, W. C.; Semple, J. E. Bioorg. Med. Chem. Lett. 1997, 7, 331.
10. (e) 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.
11. (f) Akiyama, Y.; Tsutsumi, S.; Hatsushiba, E.; Ohuchi, S.; Okonogi, T. Bioorg. Med. Chem. Lett. 1997, 7, 533.
12. (a) Smith, G. F.; Gifford-Moore, D. S.; Craft, T. J.; Chirgadze, N.; Ruterbories, K. J.; Lindstrom, T. D.; Satterwhite. J. H. In New Anticoagulants for the Cardiovascular Patient; Piffare, R., Ed.; Hanley & Belfus: Philadelphia, 1997; pp 265-300.
13. (b) Smith, G. F.; Shuman, R. T.; Craft, T. J.; Gifford-Moore, D. S.; Kurz, K D.; Jones, N. D.; Chirgadze, N.; Hermann, R. B.; Coffman, W. J.; Sandusky, G. E.; Roberts, E.; Jackson, C. V. Seminars in Thrombosis and Hemostasis, 1996, 22, 173.
14. (c) Wiley, M. R.; Chirgadze, N. Y.; Clawson, D. K.; Craft, T. J.; Gifford-Moore, D. S.; Jones, N. D.; Olkowski, J. L.; Weir, L. C.; Smith, G. F. Bioorg. Med. Chem. Lett. 1996, 6, 2387.
15. (d) Shuman, R. T.; Rothenberger, R. B.; Campbell, C. S.; Smith, G. F.; Gifford-Moore, D. S.; Gesellchen, P. D. J. Med. Chem. 1993, 36, 314.
16. (e) Jackson, C. V.; Satterwhite, J.; Roberts, E. Clin. Appl. Thrombosis/Hemostasis, 1996, 2, 258.
17. (a) Jones, C. D.; Suarez, T. US Patent 4,133,814. CAN 90:151974.
18. (b) Bastian, J. A.; Chirgadze, N. Y.; Denney, M. L.; Foglesong, R. J.; Harper, R. W.; Johnson, M. G.; Klimkowski, V. J.; Kohn, T. J.; Lin, H.-S.; Lynch, M. P.; McCowan, J. R.; Palkowitz, A. D.; Richett, M. E.; Sall, D. J.; Smith, G. F.; Takeuchi, K.; Tinsley, J. M.; Zhang, M. Int. Pat. Appl. WO 9725033. July 17, 1997. CAN 127:176339.
19. (c) Sall, D. J.; Bastian, J. A.; Briggs, S. L.; Buben, J. A.; Chirgadze, N. Y.; Clawson, D. K.; Denney, M. L.; Giera, 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.
20. Unpublished observations. 2 binds to thrombin in a similar fashion as the structure disclosed in 5c.
21. 4b Values are given as the mean of triplicate determinations, showing the standard deviation.
22. is were determined by nonlinear regression analysis using Morrison's equation for tight-binding inhibition.
23. free 28.2%). (a). Chirgadze, N. Y.; Clawson, D. K.; Gesellchen P. D.; Hermann R. B.; Kaiser R. E.; Olkowski J. L.; Sall D. J.; Schevitz R. W.; Smith G. F.; Shuman R. T.; Wery J. P.; Jones N. D. 1992, American Crystallographic Association Meeting 20: 116 [Abstr. PB311].
24. 9c are given in brackets.
25. (c). Hartley, B. S.; Shotton, D. M. In The Enzymes; Boyer, P. D., Ed.; Academic: New York, 1971; Vol. III, pp 323-373.
26. 4b by interpolating effects at different inhibitor concentrations to determine the concentration required to prolong the clotting times by two fold (values are the mean of triplicate determinations, with standard deviation).
27. Experiments with the A-V shunt model were performed with slight modifications of the methods of: Smith, J. R.; White, A. M. Br. J. Pharmac. 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.