Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 3. Enhancing activity by imposing conformational restriction in the C-4'' side chain

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 3, 1999, Pages 363-368

  Bastian, Jolie A ^a   Chirgadze, Nickolay ^a   Denney, Michael L ^a   Gifford Moore, Donetta S ^a   Sall, Daniel J ^a   Smith, Gerald F ^a   Wikel, James H ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DIAMINOBENZO[B]THIOPHENE; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; BLOOD CLOTTING; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HYDROPHOBICITY; REACTION ANALYSIS; REDUCTION; STRUCTURE ACTIVITY RELATION;

ANTITHROMBINS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; THIOPHENES;

STAPHYLOCOCCUS PHAGE 3A;

EID: 0033535105     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00746-X     Document Type: Article

References (16)

1. Preliminary accounts of this work have been presented: Sall, D. J.; Bastian, J. A.; Denney, M. L.; Gifford-Moore, D. S.; Harper, R. W.; Kohn, T. J.; Lin, H.-S.; Rampersaud, A. A.; Smith, G. F.; Takeuchi, K.; Zhang, M. Abstracts of Papers, 214th National American Chemical Society Meeting: Las Vegas, NV, Sept. 8-11th, 1997; MEDI-058.
2. For further information about the role of thrombin in blood coagulation: (a) Machovich R. In The Thrombin; Machovich, R., Ed.; CRC: Boca Raton, 1984; Vol 1; pp 1-22. (b) 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.; J. B. Lippincott Co.: Philadelphia, 1987; pp. 1063-1072. (c) Hirsh, J.; Salzman, E. W. Ibid. pp 1199-1207. (d) Barnett, H. J. M. Ibid. pp 1301-1315.
3. For further information about the role of thrombin in blood coagulation: (a) Machovich R. In The Thrombin; Machovich, R., Ed.; CRC: Boca Raton, 1984; Vol 1; pp 1-22. (b) 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.; J. B. Lippincott Co.: Philadelphia, 1987; pp. 1063-1072. (c) Hirsh, J.; Salzman, E. W. Ibid. pp 1199-1207. (d) Barnett, H. J. M. Ibid. pp 1301-1315.
4. For further information about the role of thrombin in blood coagulation: (a) Machovich R. In The Thrombin; Machovich, R., Ed.; CRC: Boca Raton, 1984; Vol 1; pp 1-22. (b) 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.; J. B. Lippincott Co.: Philadelphia, 1987; pp. 1063-1072. (c) Hirsh, J.; Salzman, E. W. Ibid. pp 1199-1207. (d) Barnett, H. J. M. Ibid. pp 1301-1315.
5. For further information about the role of thrombin in blood coagulation: (a) Machovich R. In The Thrombin; Machovich, R., Ed.; CRC: Boca Raton, 1984; Vol 1; pp 1-22. (b) 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.; J. B. Lippincott Co.: Philadelphia, 1987; pp. 1063-1072. (c) Hirsh, J.; Salzman, E. W. Ibid. pp 1199-1207. (d) Barnett, H. J. M. Ibid. pp 1301-1315.
6. For a recent review of active-site directed thrombin inhibitors: Wiley, M. R; Fisher, M. J. Exp. Opin. Ther. Patents 1997, 7, 1265.
7. 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.
8. (a) A detailed account of the X-ray crystallography studies performed on this series of thrombin inhibitors will be provided in a future publication, (b) The numbering scheme for the thrombin residues is based on topological equivalence to chymotrypsin.
9. (a) A detailed account of the X-ray crystallography studies performed on this series of thrombin inhibitors will be provided in a future publication, (b) The numbering scheme for the thrombin residues is based on topological equivalence to chymotrypsin.
10. Sall, D. J.; Briggs, S. L.; Chirgadze, N. Y.; Clawson, D. K.; Gifford-Moore, D. S.; Klimkowski, V. J.; McCowan, J. R..; Smith, G. F.; Wikel, J. H. Bioorg. Med. Chem. Lett. 1998, 8, 2527.
11. 1H NMR, MS, and IR. The experimentally determined elemental percentages of C, H, and N were within 0.4% of theoretical values. Yields were not optimized.
12. For a review of Suzuki coupling reactions: Suzuki, A. Pure Appl. Chem. 1985, 57, 1749.
13. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.
14. 1H NMR integration of olefinic protons, both cis (J = 11.8 Hz) and trans (J = 15.9 Hz) 3 were greater than 90% isomerically pure.
15. 3/THF.
16. ass) which were derived from inhibition kinetics as previously described: Smith, G. F.; Gifford-Moore, D. S.; Craft, T. J.; Chirgadze, N. Y.; Ruterbories, K. J.; Lindstrom, T. D.; Satterwhite, J. H. In New Anticoagulants for the Cardiovascular Patient, Pifarre, R., Ed.; Hanley & Belfus: Philadelphia, 1997; pp 265-300.