J. X. Qiao et al. / Bioorg. Med. Chem. Lett. 17 (2007) 1432–1437
1437
4. Pruitt, J. R.; Pinto, D. J. P.; Galemmo, R. A., Jr.;
Alexander, R. S.; Rossi, K. A.; Wells, B. L.; Drummond,
S.; Bostrom, L. L.; Burdick, D.; Bruckner, R.; Chen, H.;
Smallwood, A.; Wong, P. C.; Wright, M. R.; Bai, S.;
Luettgen, J. M.; Knabb, R. M.; Lam, P. Y. S.; Wexler, R.
R. J. Med. Chem. 2003, 46, 5298.
5. Lam, P. Y. S.; Clark, C. G.; Li, R.; Pinto, D. J. P.; Orwat, M.
J.; Galemmo, R. A.; Fevig, J. M.; Teleha, C. A.; Alexander,
R. S.; Smallwood, A. M.; Rossi, K. A.; Wright, M. R.; Bai,
S. A.; He, K.; Luettgen, J. M.; Wong, P. C.; Knabb, R. M.;
Wexler, R. R. J. Med. Chem. 2003, 46, 4405.
a relatively low Caco-2 Papp value, 16a showed good
oral bioavailability in dogs with F% = 78%. In fact,
16a showed low systematic clearance and good oral bio-
availability in dogs similar to 1 (DPC423). However, 16a
had a shorter t1/2 which may be due to its lower Vdss
.
Studies of possible metabolites of 16a, and search for
structural modifications to block or reduce the metabol-
ic pathways may improve the pharmacokinetic profile of
this series of compounds.
6. (a) Quan, M. L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.;
He, M. Y.; Li, R.; Ellis, C. D.; Clark, C. G.; Teleha, C. A.;
Sun, J.-H.; Alexander, R. S.; Bai, S.; Luettgen, J. M.;
Knabb, R. M.; Wong, P. C.; Wexler, R. R. J. Med. Chem.
2005, 48, 1729; (b) Lessen, M. R.; Davidson, B. L.; Gallus,
A.; Pineo, G.; Ansell, J.; Deitchman, D. Blood 2003, 102,
15a, Abstract 41.
7. (a) Fevig, J. M.; Cacciola, J.; Buriak, J., Jr.; Rossi, K. A.;
Knabb, R. M.; Luettgen, J. M.; Wong, P. C.; Bai, S.;
Wexler, R. R.; Lam, P. Y. S. Bioorg. Med. Chem. Lett.
2006, 16, 3755; (b) Pinto, D. J. P.; Orwat, M. J.; Quan, M.
L.; Han, Q.; Galemmo, R. A.; Amparo, E.; Wells, B.;
Ellis, C.; He, M. Y.; Alexander, R. S.; Rossi, K. A.;
Smallwood, A. M.; Wong, P. C.; Luettgen, J. M.;
Rendina, A. R.; Knabb, R. M.; Mersinger, L.; Kettner,
C.; Bai, S.; He, K.; Wexler, R. R.; Lam, P. Y. S. Bioorg.
Med. Chem. Lett. 2006, 16, 4141.
In summary, a series of pyrazole analogs bearing substi-
tuted piperidine P4 groups were synthesized and identi-
fied as potent and selective FXa inhibitors in both
monocyclic pyrazole and bicyclic pyrazolopyridine
series. The fused pyrazole analogs containing a neutral
p-methoxyphenyl P1 group showed improved FXa
inhibitory activity relative to their monocyclic counter-
parts. Compound 16a, bearing a 20-methylsulfonylphe-
nyl piperidinyl P4 group, was one of the most potent
and selective compounds prepared in this series, offering
a PK profile with low Cl and good bioavailability simi-
lar to 1 (DPC423), but a shorter t1/2
.
References and notes
8. (a) Quan, M. L.; Liauw, A. Y.; Ellis, C. D.; Pruitt, J. R.;
Bostrom, L. L.; Carini, D. J.; Huang, P. P.; Harrison, K.;
Knabb, R. M.; Thoolen, M. J.; Wong, P. C.; Wexler, R.
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2760.
9. Quan, M. L.; Han, Q.; Fevig, J. M.; Lam, P. Y. S.; Bai, S.;
Knabb, R. M.; Luettgen, J. M.; Wong, P. C.; Wexler, R.
R. Bioorg. Med. Chem. Lett. 2006, 16, 1795.
1. For review papers of FXa inhibitors, see (a) Quan, M.;
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460; (b) Walenga, J. M.; Jeske, W. P.; Hoppensteadt, D.;
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11. (a) Li, Y.-L.; Fevig, J. M.; Cacciola, J.; Buriak, J., Jr.;
Rossi, K. A.; Jona, J.; Knabb, R. A.; Luettgen, J. M.;
Wong, P. C.; Bai, S. A.; Wexler, R. R.; Lam, P. Y. S.
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P.; Galemmo, R. A.; Quan, M. L.; Orwat, M. J.; Clark,
C.; Li, R.; Woerner, F.; Wells, B.; Alexander, R. S.; Rossi,
K. A.; Smallwood, A. M.; Wong, P. C.; Luettgen, J. M.;
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Lam, P. Y. S. Bioorg. Med. Chem. Lett. 2006, 16, 4141.
12. (a) Conformational analysis was done using similar
protocols for N-cyclohexylacetamide and N-(2-meth-
ylsulfonyl)phenyl piperidine as model systems. Conforma-
tional ensembles of each model system were manually
generated in MacroModel (MMFFs force-field/GBSA
solvent model), and passed onto Jaguar for estimates of
relative conformational energies at LMP2/cc-pvtz(-f)++//
B3LYP/6-31G*; (b) MacroModel 9.0, Jaguar 6.0 Schro-
dinger, Inc., NY.
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¨
13. Analysis of small molecular crystal data relating to the
substructures of interest was done using Conquest 1.7,
3. Pinto, D. J. P.; Orwat, M. J.; Wang, S.; Fevig, J. M.;
Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.;
Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.;
Liang, L.; Aungst, B. J.; Wright, M. R.; Knabb, R. M.;
Wong, P. C.; Wexler, R. R.; Lam, P. Y. S. J. Med. Chem.
2001, 44, 566.
14. MD simulations were conducted with Discover_3 using
over
CFF98 force-field
24 ps
gas
phase.