Small, low nanomolar, noncovalent thrombin inhibitors lacking a group to fill the 'distal binding pocket'

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 2, 2003, Pages 161-164

  Sanderson, Philip E J ^a   Cutrona, Kellie J ^a   Dyer, Dona L ^a   Krueger, Julie A ^a   Kuo, Lawrence C ^a   Lewis, S Dale ^a   Lucas, Bobby J ^a   Yan, Youwei ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETAMIDE DERIVATIVE; CHLOROPHENOXYACETAMIDE P1; FUNCTIONAL GROUP; PYRIDINONE ACETAMIDE P2; PYRIDINONE ACETAMIDE P3; THROMBIN INHIBITOR; UNCLASSIFIED DRUG; ENZYME INHIBITOR; PYRIDONE DERIVATIVE; THROMBIN;

ARTICLE; CRYSTAL STRUCTURE; HYDROGEN BOND; MOLECULE; BINDING SITE; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; CRYSTALLIZATION; DRUG ANTAGONISM; HUMAN; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

ACETAMIDES; BINDING SITES; CRYSTALLIZATION; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; HUMANS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PYRIDONES; THROMBIN;

EID: 0037212115     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)00946-0     Document Type: Article

References (15)

1. (a) Sanderson P.E. J. Annu. Rep. Med. Chem. 36:2001;79.
2. (b) Coburn C.A. Exp. Opin. Ther. Pat. 11:2001;1.
3. (c) Sanderson P.E. J. Med. Res. Rev. 19:1999;179.
4. Lumma W.C., Witherup K.M., Tucker T.J., Brady S.F., Sisko J.T., Naylor-Olsen A.M., Lewis S.D., Lucas B.J., Vacca J.P. J. Med. Chem. 41:1998;1011.
5. Tucker T.J., Brady S.F., Lumma W.C., Lewis S.D., Gardell S.J., Naylor-Olsen A.M., Yan Y., Sisko J.T., Stauffer K.J., Lucas B.J., Lynch J.J., Cook J.J., Stranieri M.T., Holahan M.A., Lyle E.A., Baskin E.P., Chen I.-W., Dancheck K.B., Krueger J.A., Cooper C.M., Vacca J.P. J. Med. Chem. 41:1998;3210.
6. Sanderson P.E.J., Cutrona K.J., Dorsey B.D., Dyer D.L., McDonough C.M., 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 B.J., Lyle E.A., Lynch J.J., Stranieri M.T., Vastag K., Shafer J.A., Vacca J.P. Bioorg. Med. Chem. Lett. 8:1998;817.
7. Sanderson P.E.J., Lyle T.A., Cutrona K.J., Dyer D.L., Dorsey B.D., McDonough C.M., Naylor-Olsen A.M., Chen I.-W., Chen Z., Cook J.J., Cooper C.M., Gardell S.J., Hare T.R., Krueger J.A., Lewis S.D., Lin J.H., Lucas B.J., Lyle E.A., Lynch J.J., Stranieri M.T., Vastag K., Yan Y., Shafer J.A., Vacca J.P. J. Med. Chem. 41:1998;4466.
8. For the synthesis of these new pyridinones, see: Sanderson, P. E.; Lyle, T. A.; Vacca, J. P.; Lumma, W. C.; Brady, S. F.; Tucker, T. J. US Patent 5,792,779, 1998.
9. Sanderson P.E.J., Dyer D.L., Naylor-Olsen A.M., Vacca J.P., Gardell S.J., Lewis S.D., Lucas B.J., Lyle E.A., Lynch J.J., Mulichak A.M. Bioorg. Med. Chem. Lett. 7:1997;1497.
10. For the synthesis of these new pyrazinones see: Sanderson, P. E.; Lyle, T. A.; Dorsey, B. D.; Varsolona, R. J. US Patent 5,866,573, 1999. For an improved synthesis of the pyrazinone acetic acid core, see: Fleitz, F. J.; Lyle, T. A.; Zheng, N.; Armstrong, J. D.; Volante, R. P. Syn. Commun. 2000, 30, 3171
11. For the synthesis of these new pyrazinones see: Sanderson, P. E.; Lyle, T. A.; Dorsey, B. D.; Varsolona, R. J. US Patent 5,866,573, 1999. For an improved synthesis of the pyrazinone acetic acid core, see: Fleitz, F. J.; Lyle, T. A.; Zheng, N.; Armstrong, J. D.; Volante, R. P. Syn. Commun. 2000, 30, 3171.
12. After this work was completed, it was shown that potent pyridinones with the 3- and 4-positions linked into a second ring can be made, see: Coburn C.A., Rush D.M., Williams P.D., Homnick C., Lyle E.A., Lewis S.D., Lucas B.J., Di Muzio-Mower J.M., Juliano M., Krueger J.A., Vastag K., Chen I.-W., Vacca J.P. Bioorg. Med. Chem. Lett. 10:2000;1069. See also ref 1(b).
13. i data quoted in this report are for the human enzymes.
14. sym of 0.061 and completeness of 68%. The structure was determined using the difference Fourier method and was refined to an R factor of 0.192.
15. sym of 0.061 and completeness of 68%. The structure was determined using the difference Fourier method and was refined to an R factor of 0.192.