H. Mack et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2641–2647
2647
3. iddb3 database: Drug Report on Ximelagatran.
4. Dobesh, P. F. Pharmacotherapy 2004, 24, 169S.
5. (a) Bo¨hm, H.-J.; Koser, S.; Mack, H.; Pfeiffer, T.; Seitz,
W.; Ho¨ffken, H. W.; Hornberger, W. WO9535309; Chem.
Abstr. 1995, 124, 233168; (b) Bo¨hm, H.-J.; Ho¨ffken, H.
W.; Hornberger, W.; Koser, S.; Mack, H.; Pfeiffer, T.;
Seitz, W.; Zierke, T. WO9625426; Chem. Abstr. 1996, 125,
301605; (c) Baucke, D.; Lange, U.; Mack, H.; Seitz, W.;
Zierke, T.; Ho¨ffken, H.-W.; Hornberger, W. WO9806741;
Chem. Abstr. 1998, 128, 192940; (d) Baucke, D.; Lange,
U.; Mack, H.; Pfeiffer, T.; Seitz, W.; Zierke, T.; Ho¨ffken,
H. W.; Hornberger, W. WO9806740; Chem. Abstr. 1998,
28, 192939; (e) Baucke, D.; Lange, U.; Mack, H.; Seitz,
W.; Ho¨ffken, H. W.; Hornberger, W. WO9937611; Chem.
Abstr. 1999, 131, 116526; (f) Baucke, D.; Lange, U.; Mack,
H.; Seitz, W.; Ho¨ffken, H.-W.; Hornberger, W.
WO9937668; Chem. Abstr. 1999, 131, 116527; (g) For
synthesis details see also Ref. 10.
block 5c for the final compounds 22 and 23 (cf. Ref. 5c),
compounds 24, 31 (cf. Ref. 5f); (d) Synthesis of the
building block 5d for the final compounds 17, 29, 32 (cf.
Ref. 5f), compound 20 (cf. Ref. 5c), and compound 26 (cf.
Ref. 5e).
11. Bernard, H.; Bulow, G.; Lange, U. E. W.; Mack, H.;
¨
Pfeiffer, T.; Scha¨fer, B.; Seitz, W.; Zierke, T. Synthesis
2004, 2367.
12. (a) For in vitro assay protocols, see Ref. 5f; (b) The
standard error of the IC50 determinations was less than 1%
with r2 > 0.99 for the curve fit.
13. Nowak, G. Pathophysiol. Haemost. Thromb. 2004, 33, 173;
Nowak, G. In New Anticoagulants for the Cardiovascular
´
Patient; Pifarre, R., Ed.; Nanley & Belfus: Philadelphia,
1997; pp 539–550.
14. Measurement of ecarin clotting time (ECT): Venous blood
is collected from rats or dogs, respectively, at the desired
time after administration of the thrombin inhibitor. One
hundred microliters of citrated blood is pipetted into a
coagulation cuvette and incubated for 2 min at 37 °C in a
coagulometer. After the addition of 100 lL of prewarmed
(37 °C) ecarin reagent (Pentapharm), the time (ECT) to
formation of a fibrin clot is determined.
15. Gustafsson, D.; Antonsson, T.; Bylund, R.; Eriksson, U.;
Gyzander, E.; Nilsson, I.; Elg, M.; Mattsson, C.; Deinum,
J.; Pehrsson, S.; Karlsson, O.; Nilsson, A.; Soerensen, H.
Thromb. Haemost. 1998, 79, 110.
6. (a) Modification of the P2-moiety: Lange, U. E. W.;
Baucke, D.; Hornberger, W.; Mack, H.; Seitz, W.;
Ho¨ffken, H. W. Bioorg. Med. Chem. Lett., following
of the P3-moiety and P4-moiety: Mack, H.; Baucke, D.;
Ho¨ffken, H. W.; Hornberger, W.; Lange, U. E. W.; Seitz
W. Bioorg. Med. Chem. Lett., in preparation.
7. Wagner, G.; Horn, H.; Richter, P.; Vieweg, H.; Lischke,
I.; Kazmirowski, H. G. Pharmazie 1981, 9, 597.
8. Scha¨fer, B.; Baucke, D.; Buschmann, E.; Lange, U. E. W.;
Mack, H. Tetrahedron Lett. 1999, 40, 7067.
16. X-ray structure analysis of thrombin–inhibitor-complex of
8; X-ray crystallographic data have been deposited with
the Brookhaven Protein Data Bank. Deposition code
2ANM.
17. X-ray structure analysis of thrombin–inhibitor-complex of
10; X-ray crystallographic data have been deposited with
the Brookhaven Protein Data Bank. Deposition code
2FES.
18. X-ray structure analysis of thrombin–inhibitor-complex of
16; X-ray crystallographic data have been deposited with
the Brookhaven Protein Data Bank. Deposition code
2FEQ.
19. Lange, U. E. W.; Baucke, D.; Hornberger, W.; Mack, H.;
Seitz, W.; Ho¨ffken, H. W. Bioorg. Med. Chem. Lett. 2003,
13, 2029.
20. The authors have deposited the coordinates with the
Brookhaven Protein Data Bank: Deposition code 1O0D
(for 23) and 1NZQ (for 22).
21. Plasma levels of thrombin inhibitors were determined in
dogs by means of ex vivo measurements of ECT in plasma
(cf. Ref. 14). The ECT increases linearly with plasma
concentration and therefore provides a suitable method
9. (a) Mack, H.; Pfeiffer, T.; Seitz, W.; Zierke, T.; Balk-
enhohl, F.; Lange, U. WO9804523; Chem. Abstr. 1998,
128, 154380; (b) Scha¨fer, B.; Zierke, T. WO 9809950;
Chem. Abstr. 1998, 128, 205140; (c) Knopp, M.; Koser, S.;
Scha¨fer, B. WO0107426; Chem. Abstr. 2001, 134, 115948;
(d) Pfeiffer, T. WO 0107425; Chem. Abstr. 2001, 134,
115947; (e) Lange, U. E. W.; Zechel, C. Bioorg. Med.
Chem. Lett. 2002, 12, 1571.
10. (a) Synthesis of the building block 5a for the final
compounds 16, 19, 30, (cf. Ref. 5c), and 25 (cf. Ref. 5f);
(b) Synthesis of the building block 5b for the final
compounds 8 (cf. Ref. 5e). Compound 9 (Seitz, W.; Mack,
H.; Zierke, T.; Bo¨hm, H. J.; Ho¨ffken, H. W.; Koser, S.;
Pfeiffer, T.; Hornberger, W. WO 9624609, Chem. Abstr.
1996, 125 276585), compound 10 (Schacht, A. L.; Shuman,
R. T.; Smith, G. F.; Wiley, M. R. EP 672658; Chem. Abstr.
1995, 124, 87791), compounds 11, 22, 23, 27, 28 (cf. Ref.
5f), compounds 12, 13, 14 and 21 (cf. Ref. 5c), compound
18 (cf. Ref. 5e), compound 33 (reaction of 3-(1,3-dioxo-
1,3-dihydro-2H-isoindol-2-yl)propanal and malononitrile
with subsequent cleavage of the phthaloyl-protecting
group; unpublished results); (c) Synthesis of the building
for preliminary
assessment.
pharmacokinetic/pharmacodynamic