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3077
were also less tolerated, compound 18b was only weakly active
and compound 18a was inactive against p38 MAP kinase.
Compounds with phenylamino substituent in position 7, 3 and
2 were equally potent (compare compounds 16a–d with 19a–c and
20a,b). Replacement of the carbon linker with an oxygen linker
(X = O, compounds 21–23) altered the angle between the phenyl
rings. Only compounds with substituents at the 7 position were
tolerated, while modifications at positions 8 and 6 resulted in
weakly active compounds.
some structural determinants that may be useful for development
of future p38 MAPK inhibitors.
Acknowledgments
We thank S. Luik, M Goettert, and K. Bauer for biological testing
(p38a MAP kinase assay). Thanks also to ProQuinase GmbH for
generation of the additional kinase enzyme data (kinase assay in
16 kinases) and Kathrin E. Martz for helpful discussions.
Comparison of 16a and 21a reveals that the corresponding sub-
erones and oxepinones are equally potent. Benzoxazepinones like
compounds 24a and 24b were compared to their corresponding
suberones and oxepinones equally potent. Interestingly, the intro-
duction of an additional hydrogen bond acceptor (Y = NH) did not
result in improved activity.
Based on the favorable results with compound 16d, we varied
the distance between the two aromatic scaffolds to determine if
this extension would result in a better fit with the selectivity pock-
et. Therefore, compounds 25 and 26 were synthesized (for the syn-
thesis see Supplementary data) and compared to compound 16d.
Compound 25 was only weakly active and compound 26 was inac-
tive against p38 MAPK.
Supplementary data
Supplementary data (general synthetic procedures, spectral and
analytical data, HPLC purity and HRMS data of test compounds)
associated with this article can be found, in the online version, at
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the previously defined compound 2 (IC50 = 0.05 lM for R = NH2).
While our initial hypothesis that substitution of a tricyclic scaffold
would result in a favorable position for the carbonyl functionality
in the inhibitor was not supported by our data, we did identify
lM inhibitor-
concentration; values <20% are considered as no relevant inhibition).