304
R. A. Galemmo Jr. et al. / Bioorg. Med. Chem. Lett. 10 (2000) 301±304
of an N-sulfonyl linkage in the S4 ligand group, while
the best pharmacokinetic pro®le in rabbits is observed
for 19, an analogue with an N-(sulfonylthiophen-2-yl)-
piperidine group as the S4 ligand.
15. For a recent report of fXa inhibitors employing a cyclic
urea functionality as a part of the core structure, see: Chou,
Y.-L.; Guilford, W. J.; Koovakkat, S.; Mohan, R.; Wu, S. C.;
Liang, A.; Trinh, L.; Morrissey, M. M., Design, synthesis and
biological activity of novel factor Xa inhibitors. 10. Optimi-
zation of dibenzyl cyclic urea analogues; 215th American Che-
mical Society National Meeting (MEDI 130); 29 March 1998.
16. For full experimental details see: Maduskuie, T.; Galemmo,
Jr., R. A.; Dominguez, C.; Quan, M. L; Rossi, K. A.; Stouten,
P. F. W.; Wells, B. L. World Pat. Appl. 97/38,984.
17. Mach, R. H.; Luedtke, R. R.; Unsworth, C. D.; Boundy,
V. A.; Nowak, P. A.; Scripko, J. G.; Elder, S. T.; Jackson, J.
R.; Homan, P. L.; Evora, P. H.; Rao, A. V.; Molino, P. B.;
Childers, S. R.; Ehrenkaufer, R. L. J. Med. Chem. 1993, 36,
3707.
Acknowledgements
The authors would like to thank the following for their
technical assistance: Joseph M. Luettgen, Susan M.
Spitz, Todd C. Modzelewski, Jason J. Merrill, Elizabeth
A. Hausner, Carol Watson and Robert F. Carney.
References and Notes
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solving the inhibitor in DMSO followed by a 10-fold dilution
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sion 3.1. A System for X-ray Crystallography and NMR; Yale
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inhibitor.
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Factor Xa (ref 25) using InsightII (MSI, San Diego, CA). The
starting conformation of the inhibitor was from the crystal
structure of 10 in thrombin. The inhibitor was minimized in a
rigid protein using the CFF98 force®eld.
25. Tulinsky, A.; Padmanbhan, K.; Padmanbhan, K. P.; Park,
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