Aminomethylpyrimidines as novel DPP-IV inhibitors: A 105-fold activity increase by optimization of aromatic substituents

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 6, 2004, Pages 1491-1493

  Peters, Jens Uwe ^a   Weber, Silja ^a   Kritter, Stéphane ^a   Weiss, Peter ^a   Wallier, Angelina ^a   Boehringer, Markus ^a   Hennig, Michael ^a   Kuhn, Bernd ^a   Loeffler, Bernd Michael ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

DIPEPTIDYL PEPTIDASE IV; ENZYME INHIBITOR; PYRIMIDINE DERIVATIVE;

ARTICLE; DRUG POTENCY; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; X RAY ANALYSIS;

ADENOSINE DEAMINASE; GLYCOPROTEINS; PROTEASE INHIBITORS; PYRIMIDINES;

EID: 1542314925     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.01.019     Document Type: Article

References (27)

1. Mentlein R., Gallwitz B., Schmidt W.E. Eur. J. Biochem. 214:1993;829.
2. Kieffer T.J., McIntosh C.H.S., Pederson R.A. Endocrinology. 136:1995;3585.
3. Lene H., Deacon C.F., Orskov C., Holst J.J. Endocrinology. 140:1999;5356.
4. For a review, see: Rosenblum J.S., Kozarich J.W. Current Opinion in Chemical Biology. 7:2003;496.
5. Holst J.J. Gastroenterology. 107:1994;1048.
6. Orsakov C. Diabetologia. 35:1992;701.
7. Drucker D.J. Diabetes. 47:1998;159.
8. Ahrén B., Holst J.J., Martensson H., Balkan B. Eur. J. Pharmacol. 404:2000;239.
9. Deacon C.F., Hughes T.E., Holst J.J. Diabetes. 47:1998;764.
10. Pederson R.P., White H.A., Schlenzig D., Pauly R.P., McIntosh C.R.P., Demuth H.U. Diabetes. 47:1998;1253.
11. Pauly R.P., Rosche R., Schmidt J., White H.A., Lynn F., McIntosh C.H.S., Pederson R.A. Metabolism. 3:1999;385.
12. Pospisilik J.A., Stafford S.G., Demuth H.U., Brownsey R., Parkhouse W., Finegood D.T., McIntosh C.H.S., Pederson R.A. Diabetes. 51:2002;943.
13. Balkan B., Kwasnik L., Miserendino R., Holst J.J., Li X. Diabetologia. 42:1999;1324.
14. Mitani H., Takimoto M., Hughes T.E., Kimura M. Japanese Journal of Pharmacology. 88:2002;442.
15. Mitani H., Takimoto K.M. Japanese Journal of Pharmacology. 88:2002;451.
16. Sudre B., Broqua P., Ashworth D., Evans E.M., Haigh R., Junien J.L., Aubert M.L. Diabetes. 51:2002;1461.
17. Holst J.J., Deacon C.F. Diabetes. 47:1998;1663.
18. Zander M., Madsbad S., Madsen J.L., Holst J.J. Lancet. 359:2002;824.
19. For a review, see Drucker D.J. Expert Opinion on Investigational Drugs. 12:2003;87.
20. For a review, see: Augustyns K., Van der Veken P., Senten K., Haerners A. Expert Opin. Ther. Patents. 13:2003;499.
21. Villhauer E.B., Brinkman J.A., Naderi G.B., Dunning B.E., Mangold B.L., Mone M.D., Russell M.E., Weldon S.C., Hughes T. J. Med. Chem. 45:2002;2362.
22. Ahren B., Simonsson E., Larsson H., Landin-Olsson M., Torgeirsson H., Jansson P.A., Sandqvist M., Bavenholm P., Efendic S., Eriksson J.W., Dickinson S., Holmes D. Diabetes Care. 25:2002;869.
23. Abd-Elfattah A.M., Hussain S.M., El-Reedy A.M., Yousif N.M. Tetrahedron. 39:1983;3197.
24. For detailed procedures, see: Boehringer, M.; Loeffler, B.-M.; Peters, J.-U.; Steger, M.; Weiss, P. International Patent Application WO 03/68757, 2003.
25. 50 (×) measured for NVP-DPP728 in the assay was 11<×<19 nM.
26. Thoma R., Löffler B., Stihle M., Huber W., Ruf A., Hennig M. Structure. 11:2003;947.
27. 2. The coordinates of this structure have been deposited in the Protein Data Bank (accession code 1RWQ).