3038
P. M. Titchenell et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3034–3038
(DAA). H.D.H.S. and Y.J. acknowledge generous support by the Uni-
versity of Michigan College of Pharmacy Ella and Hans Vahlteich
Research Fund.
Supplementary data
Supplementary data (details of the chemical syntheses and as-
says performed) associated with this article can be found, in the
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(IC50 low micromolar) and cellular potency (EC50 low nanomolar) is
unclear but does not appear to be due to off-target effects as 6 has
been shown to possess excellent selectivity in a panel of 20 AGC ki-
nases and this inhibitor class has been demonstrated to not affect
canonical VEGF signaling cascades.15
Our series of phenythiophenes are the first compounds to
exhibit low nanomolar activity against aPKC activity in cells with
biomarkers of both NFjB dependent gene expression and TNF/
VEGF-induced vascular permeability. Our data suggest that the
phenylthiophene pharmacophore can be further optimized to pro-
vide therapeutic agents with the potential to treat diseases, such as
macular edema, that involve vascular permeability induced by
growth factors such as VEGF and inflammatory cytokines such as
TNF. More broadly we believe that expansion of this class can lead
to agents that target acute inflammatory responses.
Future SAR will focus on molecular modifications that further
expand upon the current series to optimize drug-like properties
while maintaining aPKC selectivity and improving potency. These
will entail modifications of the phenylthiophene core, which will
include exploration of the C-5 position. Our current studies provide
a good starting point to achieve this goal.
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Acknowledgments
This research was supported by research grants from JDRF, NIH
(R01 EY012021), and support from Research to Prevent Blindness