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EGFR potency (compound 19 vs compound 6r, IC50 = 78 vs 12 nM);
lower oral bioavailability in rats (compound 19 vs compound 6r,
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F
N
HN
N
Cl
O
S
N
CN
HN
19
In summary, a series of 2,7-diamino-thiazolo[4,5-d]pyrimidines
analogues showed modest to potent EGFR inhibition, with IC50 val-
ues ranging from micromolar to single digit nanomolar. SAR studies
of the series revealed that the preferred substituent on the 7-anilino
is a halogen such as chlorine or bromine at the meta-position, while
the 2-anilino group tolerated substitution with various solubilizing
groups. A subset of the selected compounds proved to be active
in vitro as cellular anti-proliferatives in the EGFR-over-expressing
human tumor cell line SK-OV-3. Representative compounds showed
good aqueous solubility under acidic conditions and a mixed range
of metabolic stabilities in human liver microsome preparations. Se-
lected compounds were found to have low to modest oral bioavail-
ability in rats. Further structural modification led to the discovery of
2,7-disubstituted 6-cyano-thiazolo[4,5-b]pyridines as EGFR inhibi-
tors, although these novel kinase inhibitors offered no advantage
over the 2,7-diamino-thiazolo[4,5-d]pyrimidines.
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Acknowledgments
9. (a) Binnun, E.; Johnson, S. G.; Connolly, P. J.; Middleton, S. A.; Moreno-Mazza, S.
J.; Lin, R.; Pandey, N. B.; Wetter, S. K. PCT Int. Appl., WO2007019191A2, 2007.;
(b) Lin, R.; Johnson S. G.; Connolly, P. J.; Wetter, S. K.; Binnun, E.; Hughes, T. V.;
Murray, W. V.; Adams, M.; Fuentes-Pesquera, A. R.; Pandey, N. B.; Moreno-
Mazza, S. J.; and Middleton, S. A. 236th National Meeting of the American
Chemical Society, Med. Chem. Division, August 17–21, 2008, Philadelphia, PA,
Abstract MEDI #365.
We would like to thank Dr. Jabed Seraj for assistance with
in vivo biological assays, and Alana Kriegsman for reviewing the
manuscript.
10. Wobig, D. Liebigs Ann. Chem. 1989, 409.
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