R. Kuang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2594–2597
2597
substitution with the ortho-F benzylamide on both PDE4 inhibitory
Acknowledgment
potency and selectivity (Table 3).
After introducing the (S)-methyl group to the 5-aminomethyl
moiety, all compounds in the benzylamide series in Table 3 exhibit
PDE4 inhibitory potency at the subnanomolar level. Compounds
2l, 2m, 2n, and 2s, containing the ortho-F benzylamide moiety, ex-
hibit IC50 values in the range of 30–60 pM and represent the most
potent PDE4 inhibitors reported to date. In comparing the corre-
sponding compounds from Tables 1 and 3, the (S)-methyl group
has a much greater effect on PDE4 than on PDE10 and PDE11
potency, which results in further improvement of the selectivity
for PDE4 over PDE10 and PDE11. Compound 2n is the most potent
PDE4 inhibitor with the highest relative selectivity for PDE4/PDE10
(15800-fold). This compound was chosen for profiling in our
in vivo studies.
We thank Dr. Jesse Wong, Dr. Mark Liang, and Mr. Yan Jin for
scale-up of intermediates.
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IC50 of 0.6 nM. In a rat PK study, compound 2n produces a
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and related compounds will be reported in the future.
In summary, a novel class of PDE4 inhibitors based on the qui-
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The oxazole motif, bearing the 4-carboxamide and 5-a-aminoethyl
groups, is a highly potent and unprecedented pharmacophore for
phosphodiesterase inhibition. It may also provide a new working
model for the rational design of inhibitors for other PDE enzymes.