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(b) Young, M. B.; Barrow, J. C.; Glass, K. L.; Lundell, G. F.; Newton, C. L.; Pellicore,
References and notes
J. M.; Rittle, K. E.; Selnick, H. G.; Stauffer, K. J.; Vacca, J. P.; Williams, P. D.; Bohn,
D.; Clayton, F. C.; Cook, J. J.; Krueger, J. A.; Kuo, L. C.; Lewis, S. D.; Lucas, B. J.;
McMasters, D. R.; Miller-Stein, C.; Pietrak, B. L.; Wallace, A. A.; White, R. B.;
Wong, B.; Yan, Y.; Nantermet, P. G. J. Med. Chem. 2004, 47, 2995; (c) 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. 1998, 41, 3210; (d) Lumma, W. C.;
Witherup, K. M.; Tucker, T. J.; Brady, S. F.; Sisko, J. T.; Naylor-Olsen, A. M.; Lewis,
S. D.; Freidinger, R. M. J. Med. Chem. 1998, 41, 1011.
1. (a) 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., Jr.; Lyle, E. A.; Lynch, J. J., Jr.; Stranieri, M. T.;
Vastag, K.; Shafer, J. A.; Vacca, J. P. Bioorg. Med. Chem. Lett. 1998, 8, 817; (b)
Sanderson, P. E. J.; Lyle, T. A.; Cutrona, K. J.; Dyer, D. L.; Dorsey, B. D.;
McDonough, C. M.; Naylor-Olsen, A. W.; 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. 1998, 41, 4466.
2. (a) von der Saal, W.; Heck, R.; Kucznierz, R.; Leinert, H.; Stegmeier, K. Ger. Offen.
DE 4430757 A1, 1996.; (b) Lu, T.; Illig, C. R.; Tomczuk, B. E.; Soll, R. M.;
Subasinghe, N. L.; Bone, R. F. PCT Int. Appl. WO 9711693 A1 1997.; (c) Lu, T.;
Tomczuk, B. E.; Illig, C.; Soll, R. M. PCT Int. Appl. WO 9724135 A1 1997.
3. Our involvement in this series was initiated based solely on the structures
disclosed in the original patent applications in ref 2 above. After the work
commenced, more information about compound 3 specifically (including its
thrombin potency) and this series in general, was published. See: (a) Lu, T.;
Tomczuk, B.; Illig, C. R.; Bone, R. F.; Murphy, L.; Spurlino, J.; Salemme, F. R.; Soll,
R. M. Bioorg. Med. Chem. Lett. 1998, 8, 1595; (b) Lu, T.; Tomczuk, B.; Bone, R.;
Murphy, L.; Salemme, F. R.; Soll, R. M. Bioorg. Med. Chem. Lett. 2000, 10, 83; (c)
Lu, T.; Soll, R. M.; Illig, C. R.; Bone, R.; Murphy, L.; Spurlino, J.; Salemme, F. R.;
Tomczuk, B. E. Bioorg. Med. Chem. Lett. 2000, 10, 79; (d) Tomczuk, B.; Lu, T.; Soll,
R. M.; Fedde, C.; Wang, A.; Murphy, L.; Crysler, C.; Dasgupta, M.; Eisennagel, S.;
Spurlino, J.; Bone, R. Bioorg. Med. Chem. Lett. 2003, 13, 1495.
5. (a) Kikumoto, R.; Tamao, Y.; Ohkubo, K.; Tezuka, T.; Tonomura, S.; Okamoto, S.;
Hijikata, A. J. Med. Chem. 1980, 23, 1293; (b) Kaiser, B.; Hauptmann, J.; Weiss, A.;
Markwardt, F. Biomed. Biochim. Acta 1985, 44, 1204; (c) Reers, M.; Koschinsky,
R.; Dickneite, G.; Hoffmann, D.; Czech, J.; Stuber, W. J. Enzyme Inhib. 1995, 9, 61.
6. Turner, F. A.; Gearien, J. E. J. Org. Chem. 1959, 24, 1952.
7. We consider human plasma 2 Â APTT values of 1
predictive of good in vivo efficacy with lower concentrations being predictive of
greater efficacy. We use this 1 M mark routinely as a gate for determining
lM or less to be generally
l
whether to evaluate a compound further in vivo in the rat ferric chloride efficacy
assay (see Ref. 4). In practice, in optimizing compounds, we strive to achieve
2 Â APTT values of <0.5
lM.
8. For a discussion of the role of lipophilicity in modulating the functional potency
of thrombin inhibitors see: Tucker, T. J.; Lumma, W. C.; Mulichak, A. M.; Chen, Z.;
Naylor-Olsen, A. M.; Lewis, S. D.; Lucas, R.; Freidinger, R. M.; Kuo, L. C. J. Med.
Chem. 1997, 40, 830.
4. (a) Isaacs, R. C. A.; Solinsky, M. G.; Cutrona, K.; Newton, C. L.; Naylor-Olsen, A.
M.; Krueger, J. A.; Lewis, S. D.; Lucas, B. J. Bioorg. Med. Chem. Lett. 2006, 16, 338;