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M. T. Bilodeau et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2485–2488
provide 7. This alkylation provides a 4:1 ratio of N- and
O-alkylation products.
11. Fraley, M. E.; Hoffman, W. F.; Rubino, R. S.; Hungate,
R. W.; Tebben, A. J.; Rutledge, R. Z.; McFall, R. C.; Huckle,
W. R.; Kendall, R. L.; Coll, K. E.; Thomas, K. A. Bioorg.
Med. Chem. Lett. 2002, 12, 2767.
We have described the development of 1,5-diarylbenz-
imidazoles that are potent and selective KDRinhibi-
tors. These compounds significantly improved physical
properties relative to the corresponding 3,6-diarylpyr-
azolo[1,5-a]pyrimidines. In particular, 3 and 7 have
excellent potency and pharmacokinetic profiles. The
pyridone 7 additionally has a significantly improved
LogP and solubility, properties which may confer
advantages in vivo.
12. Fraley, M. E.; Rubino, R. S.; Hoffman, W. F.; Ham-
baugh, S. R.; Arrington, K. L.; Hungate, R. W.; Bilodeau,
M. T.; Tebben, A. J.; Rutledge, R. Z.; Kendall, R. L.; McFall,
R. C.; Huckle, W. R.; Coll, K. E.; Thomas, K. A. Bioorg.
Med. Chem. Lett. 2002, 12, 3537.
13. All target compounds were fully characterized by 1H
NMRand mass spectroscopy.
14. The KDRIC value represents biochemical inhibition of
50
phosphorylation of a poly-Glu/Tyr (4:1) peptide substrate by
isolated KDRkinase (cloned and expressed as a GST-fusion
protein): see, Kendall, R. L.; Rutledge, R. Z.; Mao, X.; Teb-
ben, A. L.; Hungate, R. W.; Thomas, K. A. J. Biol. Chem.
1999, 274, 6453. Values are reported as single determinations
or as the average of at least two determinationsÆstandard
deviation.
15. N-Aryl benzimidazoles as inhibitors of PDGF: Palmer,
P. D.; Smaill, J. B.; Boyd, M.; Boschelli, D. H.; Doherty,
A. M.; Hamby, J. M.; Khatana, S. S.; Kramer, J. B.; Kraker,
A. J.; Panek, R. L.; Lu, G. H.; Dahring, T. K.; Winters, R. T.;
Showalter, H. D. H.; Denny, W. A. J. Med. Chem. 1998, 41,
5457.
16. The Cell IC50 value represents the inhibition of VEGF-
stimulated mitogenesis as determined in human umbilical vein
endothelial cells. For the key compounds 3, 4 and 7 the
averages are based on 3, 34 and 7 determinations respectively.
17. Partition coefficients were determined by adding an ali-
quot of a methanolic sample solution to equal volumes of 1-
octanol and pH 7.4 buffer and measuring the concentration in
each after an equilibration period of 8 h. Buffer solubilities
were determined by comparing the HPLC peak area of a fil-
tered, saturated solution of compound in pH adjusted buffer
to peaks from standard methanolic solutions. Protein binding
to human plasma is determined by equilibrating buffer solu-
tions of test compounds and human plasma and using ultra-
filtration for separation. The free compound concentration is
measured by HPLC.
18. Traxler, P.; Furet, P. Pharmacol. Ther. 1999, 82, 195.
19. Compound 4 was prepared according to the synthesis of 3,
beginning with 5-bromo-2-chloro-3-nitropyridine. Com-
pounds 5, 8 and 10 were derived from alkyation of 5-iodo-
pyridin-2-ol and subsequent coupling with the boronate ester
in Scheme 2. Compound 6 was prepared by coupling of the
boronate ester with 5-bromo-2-fluoropyridine and displace-
ment of the resulting fluoride with (2-morpholin-4-ylethyl)-
amine. Compound 9 was prepared according to the synthesis
of 7, using the homologous alkylating reagent. Compound 11
was prepared by coupling of the boronate ester with 4-chloro-
2-(methylthio)pyrimidine, followed by hydrolysis of the thio-
methyl-functionality and alkylation according to Scheme 2.
Acknowledgements
We thank Matthew M. Zrada and Kenneth D.
Anderson for LogP, solubility and protein binding
determinations.
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