6668 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27
Letters
(8) Myoui, A.; Nishimura, R.; Williams, P. J.; Hiraga, T.; Tamura,
D.; Michigami, T.; Mundy, G. R.; Yoneda, T. C-Src tyrosine
kinase activity is associated with tumor colonization in bone and
lung in an animal model of human breast cancer metastasis.
Cancer Res. 2003, 63, 5028-5033.
(9) Susva, M.; Missbach, M.; Green, J. Src inhibitors: Drugs for the
treatment of osteoporosis, cancer or both? Trends Pharmacol.
Sci. 2000, 21, 489-495.
(10) Paul, R.; Zhang, Z. G.; Eliceiri, B. P.; Jiang, Q.; Boccia, A. D.;
Zhang, R. L.; Chopp, M.; Cheresh, D. A. Src deficiency or
blockade of Src activity in mice provides cerebral protection
following stroke. Nat. Med. 2001, 7, 222-227.
(11) Boschelli, D. H.; Wang, Y. D.; Ye, F.; Wu, B.; Zhang, N.; Dutia,
M.; Powell, D. W.; Wissner, A.; Arndt, K.; Weber, J. M.; Boschelli,
F. Synthesis and Src kinase inhibitory activity of a series of
4-phenylamino-3-quinolinecarbonitriles. J. Med. Chem. 2001, 44,
822-833.
(12) Boschelli, D. H.; Ye, F.; Wang, Y. D.; Dutia, M.; Johnson, S. L.;
Wu, B.; Miller, K.; Powell, D. W.; Yaczko, D.; Young, M.; Tischler,
M.; Arndt, K.; Discafani, C.; Etienne, C.; Gibbons, J.; Grod, J.;
Lucas, J.; Weber, J. M.; Boschelli, F. Optimization of 4-pheny-
lamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase
activity. J. Med. Chem. 2001, 44, 3965-3977.
(13) Boschelli, D. H. Y., F.; Wu, B.; Wang, Y. D.; Barrios Sosa, A. C.;
Yaczko, D.; Powell, D.; Golas, J. M.; Lucas, J.; Boschelli, F.
Investigation of the effect of varying the 4-anilino and 7-alkoxy
groups of 3-quinolinecarbonitriles on the inhibition of src kinase
activity. Bioorg. Med. Chem. Lett. 2003, 13, 3797-3800.
(14) Golas, J. M.; Arndt, K.; Etienne, C.; Lucas, J.; Nardin, D.;
Gibbons, J.; Frost, P.; Ye, F.; Boschelli, D. H.; Boschelli, F. SKI-
606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and
Abl kinases, is a potent antiproliferative agent against chronic
myelogenous leukemia cells in culture and causes regression of
K562 xenografts in nude mice. Cancer Res. 2003, 63, 375-381.
(15) Boschelli, D. H.; Wang, Y. D.; Johnson, S.; Wu, B.; Ye, F.; Barrios
Sosa, A. C.; Golas, J. M.; Boschelli, F. 7-Alkoxy-4-phenylamino-
3-quinolinecarbonitriles as dual inhibitors of Src and Abl ki-
nases. J. Med. Chem. 2004, 47, 1599-1601.
series where an analogue with a morpholinomethyl
group at the ortho position was about 3 log orders less
potent than the para isomer.17
A dramatic difference in activity was also observed
between 13, the C-2 substituted thieno[2,3-b]pyridine,
and 22, its C-3 isomer. While 13 had an IC50 of 34 nM
in the Src enzyme assay, 22 had an IC50 of greater than
10 µM. A more modest decrease in potency was observed
with 30, the thieno[2,3-b]pyridine analogue of 13, which
had an IC50 of 830 nM in the Src enzyme assay.
As was observed in the 3-quinolinecarbonitrile series,
the 7-phenylamino analogue 37 was a more potent Src
inhibitor than the corresponding 7-phenoxy 38 or 7-ben-
zylamino 39 analogues. Furthermore, as was seen
previously, 37, which lacks the 5-OMe group on the
aniline, was about 1/4 as active as 14, which contains
the preferred 2,4-dichloro-5-methoxyaniline group.
Compound 14 was tested against a panel of kinases.
While IC50s of greater than 1 µM were observed against
KDR, CDK4, and raf/MEK, 14 was a potent inhibitor
of Abl kinase, having an IC50 of 2.3 nM. This inhibition
of Abl activity by 14 was not unexpected since several
3-quinolinecarbonitriles are also dual inhibitors of Src
and Abl, with SKI-606 having an IC50 of 1.1 nM for Abl
inhibition.14,15
We are continuing to investigate the biological prop-
erties of 14 and expanding the SAR of this new core for
Src kinase inhibitors.
Acknowledgment. We thank the Wyeth Discovery
Analytical Chemistry Department for the spectral data
and combustion analysis. We also thank Drs. Dennis
Powell and Tarek Mansour for their support of this
work.
(16) Boschelli, D. H.; Wang, D. Y.; Ye, F.; Yamashita, A.; Zhang, N.;
Powell, D.; Weber, J.; Boschelli, F. Inhibition of Src kinase
activity by 4-anilino-7-thienyl-3-quinolinecarbonitriles. Bioorg.
Med. Chem. Lett. 2002, 12, 2011-2014.
(17) Berger, D.; Dutia, M.; Powell, D.; Wissner, A.; DeMorin, F.;
Raifeld, Y.; Weber, J.; Boschelli, F. Substituted 4-anilino-7-
phenyl-3-quinolinecarbonitriles as Src kinase inhibitors. Bioorg.
Med. Chem. Lett. 2002, 12, 2989-2992.
(18) Barrios Sosa, A. C.; Boschelli, D. H.; Ye, F.; Golas, J. M.;
Boschelli, F. Synthesis and inhibition of Src kinase activity by
7-ethenyl and 7-ethynyl-4-anilino-3-quinolinecarbonitriles. Bioorg.
Med. Chem. Lett. 2004, 14, 2155-2158.
(19) Munchhof, M. J.; Beebe, J. S.; Casavant, J. M.; Cooper, B. A.;
Doty, J. L.; Higdon, R. C.; Hillerman, S. M.; Soderstrom, C. I.;
Knauth, E. A.; Marx, M. A.; Rossi, A. M. K.; Sobolov, S. B.; Sun,
J. Design and SAR of thienopyrimidine and thienopyridine
inhibitors of VEGFR-2 kinase activity. Bioorg. Med. Chem. Lett.
2004, 14, 21-24.
(20) Thompson, M.; Forbes, I. T. Anxiolytic and antidepressant
thienopyridine derivatives. EP 126970; Chem. Abstr. 1985, 102,
220869.
Supporting Information Available: Experimental de-
tails, 1H NMR, HRMS, and analytical data for all compounds.
This material is available free of charge via the Internet at
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