Derivatives of 4-amino-pyridine as selective thrombin inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 10, 1997, Pages 1283-1288

  Von der Saal, Wolfgang ^a   Kucznierz, Ralf ^a   Leinert, Herbert ^a   Engh, Richard A ^b  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

^b MAX PLANCK INSTITUTE OF BIOCHEMISTRY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOPYRIDINE DERIVATIVE; PLASMIN; THROMBIN; THROMBIN INHIBITOR; TRYPSIN;

ANIMAL TISSUE; ARTICLE; CATTLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG SYNTHESIS; ENZYME BINDING; ENZYME INHIBITION; ENZYME SPECIFICITY; HUMAN; HUMAN TISSUE; HYDROPHOBICITY; IN VITRO STUDY; MODEL; NONHUMAN; PKA; STRUCTURE ACTIVITY RELATION;

EID: 0031579970     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00210-2     Document Type: Article

References (22)

1. Stone, S.R. Trends Cardiovasc. Med. 1995, 5, 134. Verstraete, M.; Zoldhely, P. Drugs 1995, 49, 856; Das, J.; Kimball, S.D. Bioorganic. Med. Chem., 1995, 3, 999.
2. Stone, S.R. Trends Cardiovasc. Med. 1995, 5, 134. Verstraete, M.; Zoldhely, P. Drugs 1995, 49, 856; Das, J.; Kimball, S.D. Bioorganic. Med. Chem., 1995, 3, 999.
3. Stone, S.R. Trends Cardiovasc. Med. 1995, 5, 134. Verstraete, M.; Zoldhely, P. Drugs 1995, 49, 856; Das, J.; Kimball, S.D. Bioorganic. Med. Chem., 1995, 3, 999.
4. Bode W., Mayr I., Baumann U., Huber R., Stone S.R., Hofsteenge J. EMBO J. 8:1989;3467.
5. Kimball S.D. Curr. Pharm. Design. 1:1995;441.
6. 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. 6:1996;2387.
7. For a recent review on the design principles for orally bioavailable drugs see: Navia, M.A.; Chaturvedi, P.R. Drug Discovery Today 1996, 1, 179.
8. The benzamidine derivative NAPAP (12) has Ki = 6 nM, while its benzylamine analog has Ki = 19 μM: Stürzebecher, J.; Horn, H.; Walsmann, P.; Voigt, B.; Markwardt, F.; Wagner, G. Pharmazie 1988, 43, 782. The boro-arginine thrombin inhibitor DuP 714 has Ki = 0.04, while its boro-lysine derivative has Ki = 0.24: Cacciola, J.; Fevig, J.M.; Alexander, R.S.; Brittelli, D.R.; Kettner, C.A.; Knabb, R.M.; Weber, P.C. Bioorg. Med. Chem. Lett. 1996, 6, 301.
9. The benzamidine derivative NAPAP (12) has Ki = 6 nM, while its benzylamine analog has Ki = 19 μM: Stürzebecher, J.; Horn, H.; Walsmann, P.; Voigt, B.; Markwardt, F.; Wagner, G. Pharmazie 1988, 43, 782. The boro-arginine thrombin inhibitor DuP 714 has Ki = 0.04, while its boro-lysine derivative has Ki = 0.24: Cacciola, J.; Fevig, J.M.; Alexander, R.S.; Brittelli, D.R.; Kettner, C.A.; Knabb, R.M.; Weber, P.C. Bioorg. Med. Chem. Lett. 1996, 6, 301.
10. For a recent review on the methods of structure based drug design see: Böhm, H.-J.; Klebe, G. Angew. Chem. 1996, 108, 2750; Angew. Chem. Int. Ed. Engl. 1996, 35, 2588.
11. For a recent review on the methods of structure based drug design see: Böhm, H.-J.; Klebe, G. Angew. Chem. 1996, 108, 2750; Angew. Chem. Int. Ed. Engl. 1996, 35, 2588.
12. Brandstetter H., Turk D., Hoeffken W., Grosse D., Stürzebecher J., Martin P.D., Edwards B.F.P., Bode W. J. Mol. Biol. 226:1992;1085.
13. Dega-Szafran Z., Kania A., Nowak-Wydra B., Szafran M. J. Mol. Struct. 322:1994;223.
14. Numbering of thrombin residues is based on that for chymotrypsinogen, and the subsite nomenclature of Banner et al. is used: Banner, D.W.; Hadváry, P. J. Biol. Chem. 1991, 266, 20085.
15. The inhibition constants were determined as described in: von der Saal, W.;Engh, R.A.; Eichinger, A.; Gabriel, B.; Kucznierz, R.; Sauer, J. Arch. Pharm. Pharm. Med. Chem. 1996, 329, 73.
16. The Ki values of benzamidine are taken from Markwardt, F.; Landmann, H.; Walsmann, P. Eur. J. Biochem. 1968, 6, 502.
17. Stürzebecher J., Markwardt F., Walsmann P., Voigt B., Wagner G. Pharmazie. 42:1987;114.
18. Roberts, S.M.; Suschitzky, H. J. Chem. Soc. C 1968, 2844.
19. Engh R.A., Brandstetter H., Sucher G., Eichinger A., Baumann U., Bode W., Huber R., Poll T., Rudolph R., von der Saal W. Structure. 4:1996;1353.
20. Lorand L., Rule N.G. Nature (London). 190:1961;722.
21. Wiley M.R., Chirgadze N.Y., Clawson D.K., Craft T.J., Gifford-Moore D.S., Jones N.D., Olkowski J.L., Schacht A.L., Smith G.F., Weir L.C. Bioorg. Med. Chem. Lett. 5:1995;2835.
22. PDB ID code 1 PPC: Bode, W.; Turk, D.; Stüzebecher, J. Eur. J. Biochem. 1990, 193, 175.