1746
A. C. Barrios Sosa et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1743–1747
increased Src inhibitory activity over their 6-H analogs
18a and 19a. Moreover, 7-ethenylimidazole 19b exhib-
ited an IC50 value of 39 nM in a Src dependent cell pro-
liferation assay, which represents a 2-fold increase in
potency over the 7-ethenylpyridine 2a (Table 2).
addition, the plasma levels of 19b were below the quan-
tification limit of 5 ng/mL. In order to improve the bio-
availability of this class of Src inhibitors, future efforts
will focus on the synthesis of analogs where water solu-
bilizing amine groups have been introduced onto the
pyridine ring, as in the case of 21. Our findings with
these new derivatives will be reported in due course.
Finally, the synthesis of 1-oxidopyridine analogs was
investigated to determine if oxidation of the pyridine
nitrogen would have an effect on the ability of the com-
pound to inhibit Src. As shown in Scheme 5, 4-vinylpyr-
idine 2b was treated with mCPBA at room temperature
to provide derivative 20a, which exhibited a 2-fold in-
crease in inhibitory activity, both in the enzyme and cell
assays, compared to its parent compound 2b (Tables 1
and 2). Since the 6-OMe analog of 20a was expected
to show improved potency, the synthesis of N-oxide
20b was pursued next. In this case, intermediate 17
was treated with 4-vinylpyridine N-oxide6 to give the de-
sired product. This route, which circumvents the forma-
tion of over oxidized products, was also used for the
synthesis of analog 20c, which bears a 3,4,5-triOMe ani-
line group at C-4.
Cl
Cl
O
HN
O
CN
R
N
N
R'
N
21
Acknowledgements
We thank Dr. Nan Zhang and Minu Dutia for the prep-
aration of intermediates 5a,b and 5d, Deanna Yaczko
and Judy Lucas for PK analysis, and members of
the Wyeth Discovery Analytical Chemistry group for
spectral data and elemental analyses. We also thank
Drs. Dennis Powell and Tarek Mansour for their
support, and Dr. Frank Boschelli for critical comments
on the manuscript.
N-oxide 20b exhibited a subnanomolar IC50 value in the
enzyme assay (IC50 = 0.6 nM), making it the most po-
tent 3-quinolinecarbonitrile Src inhibitor reported to
date. In addition, analog 20b showed an IC50 value of
16 nM in the Src dependent cell proliferation assay,
which represents more than a 4-fold increase in potency
compared to its unoxidized analog 2a. Analog 20c, on
the other hand, was approximately 20-fold less potent
than 20b in the enzyme assay. However, this analog
showed improved enzyme inhibitory activity compared
to its unoxidized derivative 10b.
References and notes
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Frame, M. C. Biochem. Biophys. Acta 2002, 1602, 114; (c)
Metcalf, C. A., III; van Schravendijk, M. R.; Dalgarno, D.
C.; Sawyer, T. K. Curr. Pharm. Des. 2002, 8, 2049; (d)
Courtneidge, S. A. Biochem. Soc. Trans. 2002, 30, 11; (e)
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Johnson, S.; Wu, B.; Miller, K.; Powell, D. W.; Arndt, K.;
Discafani, C.; Etienne, C.; Gibbons, J.; Grod, J.; Lucas, J.;
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(b) Golas, J. M.; Arndt, K.; Etienne, C.; Lucas, J.; Nardin,
D.; Gibbons, J.; Frost, P.; Ye, F.; Boschelli, D. H.;
Boschelli, F. Cancer Res. 2003, 63, 375.
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Derivatives with the best potency, namely 2a, 19b and
20b, were selected for a PK study. Twenty-four hours
after administration of a single oral 50 mg/kg dose to
nude mice, plasma concentrations of 19 and 20 ng/mL
were measured for 2a and 20b, respectively. These values
are approximately half the plasma concentration deter-
mined for 1 (40 ng/mL) under the same conditions. In
Cl
Cl
O
Cl
Cl
O
HN
HN
a
CN
CN
N
N
N
2b
N
20a
O
R
R
HN
HN
b
Y
CN
Y
X
CN
N
N
N
O
20b: Y = OMe, R = 2,4-diCl, 5-OMe
20c: Y = H, R = 3,4,5-triOMe
17: X = OTf, Y = OMe,
R = 2,4-diCl, 5-OMe
5d: X = Br, Y = H,
R = 3,4,5-triOMe
Scheme 5. Reagents and conditions: (a) mCPBA, dichloromethane,
AcOH; (b) 4-vinylpyridine N-oxide, Pd(OAc)2, P(o-Tol)3, DMF, TEA.
5. Barrios Sosa, A. C.; Boschelli, D. H.; Ye, F.; Golas, J. M.;
Boschelli, F. Bioorg. Med. Chem. Lett. 2004, 14, 2155.