5540
K. J. Moriarty et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5537–5540
Table 5
References and notes
Cellular activity, cytotoxicity and microsome stability of selected compounds
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Compound Itk IC50
M)
DT40 IC50
M)
Jurkat TC50
(lM)
HLM CLH
(%QH)
RLM CLH
(%QH)
(
l
(
l
4. Schaeffer, E. M.; Debnath, J.; Yap, G.; McVicar, D.; Liao, X. C.; Littman, D. R.;
Sher, A.; Varmus, H. E.; Lenardo, M. J.; Schwartzberg, P. L. Science 1999, 284,
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10
19
27
0.003
0.006
0.007
0.34
0.34
0.16
>10
5.8
>10
32
48
57
35
46
nd
nd, not determined.
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Table 6
Selectivity results of selected compounds
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Ericsson, P. O.; Erjefalt, J. S. Am. J. Respir. Cell. Mol. Biol. 2005, 32, 511.
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Compound IRK IC50 Lyn IC50 Tec IC50
Txk IC50
M)
Cyp 2C9
M)
Cyp 3A4
(lM)
(l
M) M) M)
(
l
(
l
(
l
(
l
10
19
27
>10
>10
>10
>10
>10
>10
>10
>10
>10
0.56
0.50
0.31
>30
>30
>30
>30
>30
>30
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submitted for publication.
good cellular potency in the DT40 cellular assay. All the com-
pounds exhibited improved stability compared to 2 against human
microsomes, and greater than 500-fold separations between the
DT40 IC50 and TC50 values. The compounds also showed excellent
selectivity against IRK, Lyn, Tec and a 44- to 188-fold selectivity
against Txk. Unfortunately although the compounds did show an
improvement there still was a high degree of metabolism indicat-
ing additional susceptible sites on the compounds. There was how-
ever an observed 2-fold improvement when the N–CH3 was
replaced with a N–Et which did point to one of the possible sites
of metabolism for the series. Additional profiling is currently
underway to identify the other sites so additional corrective mod-
ifications can be carried out to improve the stability of the series.
In summary, starting from a series that showed excellent enzy-
matic potency and selectivity but poor microsomal stability, we
identified a new series that retained excellent potency, selectivity
and cellular activity and with the potential for improved micro-
some stability. Further improvements and modifications of the ser-
ies focusing on improving the stability and leading to an orally
active Itk inhibitor will be presented in forthcoming publications.
18. Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29, 1159.
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