P. E. J. Sanderson et al. / Bioorg. Med. Chem. Lett. 13 (2003) 795–798
797
Table 2. Final assay concentration of compound required to double
the human activated partial thromboplastin time (2ÂAPTT)12 and
pharmacokinetic parameters in dogs after oral administration at 1mg/
kg
2. Chen, Z.; Li, Y.; Mulichak, A. M.; Lewis, S. D.; Shafer,
J. A. Arch. Biochem. Biophys. 1995, 322, 198.
3. Paradoxically, addition of an ortho chloro substituent to
arylamidine serine protease inhibitors was shown to increase
selectivity for Ser-190 proteases over Ala-190 proteases. This
was ascribed to the loss of a hydrogen bond from an ordered
water molecule to the amidine which could be compensated by
the side chain of Ser-190 but not by that of Ala-190: Mack-
man, R. L.; Katz, B. A.; Breitenbucher, J. G.; Hui, H. C.;
Verner, E.; Luong, C.; Liu, L.; Sprengeler, P. A. J. Med.
Chem. 2001, 44, 3856. Katz, B. A.; Sprengeler, P. A.; Luong,
C.; Verner, E.; Elrod, K.; Kirtley, M.; Janc, J.; Spencer, J. R.;
Breitenbucher, J. G.; Hui, H.; McGee, D.; Allen, D.; Martelli,
A.; Mackman, R. L. Chem. Biol. 2001, 8, 1107.
Compd 2ÂAPTT mM Dog Cmax (mM) t1=2 (h) AUC (mM h)
1
0.41
0.80
2.63
0.40
0.95
5.37
blqa
2.69
0.18
2.10
3.18
—
3.60
ndb
2.42
23.1
—
15.2
0.17
9.1
8b
9a
9b
10b
aBelow the level of quantitation.
bNot determined due to insufficient data.
4. Kikumoto, R.; Tamao, Y.; Ohkubo, K.; Tezuka, T.;
Tonomura, S.; Okamoto, S.; Hijikata, A. J. Med. Chem. 1980,
23, 1293. Kaiser, B.; Hauptmann, J.; Weiss, A.; Markwardt,
F. Biomed. Biochim. Acta 1985, 44, 1204. Reers, M.;
Koschinsky, R.; Dickneite, G.; Hoffmann, D.; Czech, J.; Stu-
ber, W. J. Enzyme Inhib. 1995, 9, 61.
5. (a) Sanderson, P. E. J.; Lyle, T. A.; Cutrona, K. J.; Dyer,
D. L.; Dorsey, B. D.; McDonough, C. M.; Naylor-Olsen,
A. M.; 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. (b) 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.; Lyle, E. A.; Lynch,
J. J.; Stranieri, M. T.; Vastag, K.; Shafer, J. A.; Vacca, J. P.
Bioorg. Med. Chem. Lett. 1998, 8, 817.
The affinity of the azaindole derivatives for thrombin
correlates with the acidity of the conjugate acids of the
parent azaindoles.17 Thus, while 7-azaindole derivative
10a is equipotent to indole 5a, 4-azaindole 8a is slightly
more potent and 6-azaindole 9a is the most potent
(Ki=3.7 nM). Satisfyingly, despite the addition of a
polar functional group, all three azaindoles remained
highly selective. To improve the activity of the com-
pounds, the corresponding3-[(2-pyridin-2-ylethyl]ami-
no)pyrazinones 8b, 9b, and 10b were made and in each
case a roughly three-fold improvement in the Ki was
8
seen alongwith better selectivity versus trypsin.
The potent azaindoles were examined in more depth for
their efficacy in vitro (2ÂAPTT) and for their pharma-
cokinetic parameters after oral administration in dogs
(Table 2). Compound 9a was well absorbed in dogs and
was comparable to compound 1.5a However, it was
poorly efficacious in vitro. On the other hand pyridine
9b was as efficacious as 1 in vitro but was absorbed very
poorly. 7-Azaindole 10b had intermediate properties
with moderate efficacy and oral absorption, while
4-azaindole 8b was moderately efficacious but was not
absorbed in dogs.
6. It should be noted that the absolute affinity of 1 for trypsin
is adequate (Ki=1.8 mM) given its solubility (1.6 mg/mL 10
mM citrate buffer, pH 7.0, 23 ꢀC).
7. Imidazopyridines 2–4 were prepared by treatment of the
correspondingaminopyridine with bromoacetaldehyde and
potassium acetate in water/acetic acid/DMF, see: Sanderson,
P. E., Naylor-Olsen, A. M. US Patent 6,093,717, 2000.
8. For the synthesis of compounds 5 and 7–10 see: Sanderson,
P. E.; Lyle, T. A.; Dorsey, B. D., Stanton, M. G., Staas, D.,
Coburn, C., Naylor-Olsen, A. M., Morrissette, M. M., Sel-
nick, H. G., Nantermet, P. G., Williams, P. D., Stauffer, K. J.,
Burgey, C., Isaacs, R. Barrow, J. C. WO2000026211, 2000.
5-Aminomethylindole and 5-aminomethylbenzimidazole are
commercially available.
9. Similar indoles, indazoles, benzimidazoles and benzo-
triazoles havinga single basic center with p Ka greater than 6
have been claimed as antithrombotic agents: Blagg, J.; Brown,
A. D.; Gautier, E. C. L.; Smith, J. D.; McElroy, A. B. US
Patent 6,180,627, 2001.
In conclusion, we have developed a series of moderately
basic azaindole P1 groups which are intrinsically much
more selective than the aminopyridine P1 group of
compound 1. Certain of these azaindole derivatives
have pharmacokinetic parameters after oral adminis-
tration to dogs, or efficacy in vitro, comparable to
compound 1. The challenge remains to find a compound
which combines these latter properties in the same
molecule.
10. For the synthesis of compound 6 see: Sanderson, P. E.;
Lyle, T.; Dorsey, B.; Stanton, M.; Naylor-Olsen, A. M. US
Patent 6,376,499, 2002. 6-Aminomethylindole is commercially
available.
11. Amides of benzimidazolylalanine have been claimed to
inhibit thrombin induced coagulation: Heckel, A.; Sauter, R.;
Psiorz, M; Binder, K.; Mueller, T.; Zimmermann, R. US
Patent 5,391,556, 1995.
Acknowledgements
We thank Orn Almarsson for performingthe p Ka and
solubility determinations for compound 1 and Dan
McMasters for his help with the figures.
12. Lewis, S. D.; Ng, A. S.; Baldwin, J. J.; Fusetani, N.;
Naylor, A. M.; Shafer, J. A. Thromb. Res. 1993, 70, 173. All
the Ki data quoted in this report are for the human enzymes.
13. The 2-pyridin-2-ylethyl side chain was originally devel-
oped in the aminopyridine P1 series: Sanderson, P. E. J., Lyle,
T. A., Dorsey, B. D., Varsolona, R. J. US Patent 5,866,573,
1999. For its characterization in the aminopyridine series see:
Burgey, C. S.; Robinson, K. A.; Lyle, T. A.; Sanderson, P. E.
J.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Singh, R.; Miller-
Stein, C.; White, R. B.; Wong, B.; Lyle, E. A.; Williams, P. D.;
References and Notes
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