3158
A. S. Rosenthal et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3152–3158
Table 4
Aqueous solubility and stability and Caco-2 permeability data for selected agents
Analogue
Kinetic solubilitya
(l
M)
Papp (A–B)b (10ꢁ6 cm/s)
Papp (B–A)b (10ꢁ6 cm/s)
48 h aqueous stabilityc
(DPBS buffer, pH 7.4)
45
46
54
4.3
6.6
143.3
25.5
18.9
35.4
12.7
8.9
23.1
>95
>95
>95
a
b
c
Aqueous stability measured over 48 h in pH 7.4 DPBS buffer. Value reflects the % remaining.
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for the potency decrease versus Dyrk1A and Dyrk1B (>10,000 and
4420 nM, respectively). This interaction also highlights a potential
route to furthering the SAR of this chemotype.
As it was our goal to define probe compounds for these targets
that would have use within cell-based studies it was important for
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aqueous solubility data (Analiza, Inc.) and Caco-2 permeability
data (Cyprotex PLC). We further examined the stability of these
agents in aqueous buffered environment for 48 h (results are based
upon retention of UV/Vis signal and mass assessment within a
standard HPLC gradient). The outcome of these studies is shown
in Table 4. Compounds 45 and 46 were found to possess only mod-
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file suggested that each agent was capable of passive membrane
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was highly stable in an aqueous environment for up to 48 h.
In conclusion, the expansion of our previous efforts surrounding
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Dyrk1A below 100 nM. A broad kinome scan has confirmed that
these compounds are highly selective for these targets and molec-
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hinge region. This work also defined the first reported inhibitor
of Dyrk1B. These agents provide useful tool compounds to probe
the role of these targets in pre-mRNA splicing and, in the case of
Dyrk1B, specified roles in cancer.
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Acknowledgments
We greatly appreciate the assistance of William Leister and
Thomas Daniel for compound analysis and purification and Chris
LeClair, Paul Shinn and Danielle VanLeer for compound manage-
ment. This research was supported by the Molecular Libraries Ini-
tiative of the National Institutes of Health Roadmap for Medical
Research and the Intramural Research Program of the National Hu-
man Genome Research Institute.
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Supplementary data
Supplementary data associated with this article can be found, in
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