622
M. C. Bryan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 619–622
while maintaining potency in the meta-series coupled with the
ability to reverse inflammatory pain in vivo with compound 15
of the para-series highlight the potential of the chromenones rela-
tive to the previously reported phthalazinone series. Additional
exploration of this viable alternate scaffold for the inhibition of
bradykinin B1-mediated pain is in progress.
References and notes
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Figure 2. Efficacy of chlorochromenone 15 in
a rabbit carrageenan model of
inflammatory pain. Vehicle: 25% captisol/water, pH 3.4; Cmpd 15 dosed s.c. at
10 mpk at 60 min before testing; ⁄⁄P < 0.01, one-way ANOVA, followed by Dunnett’s
post-hoc multiple comparison test, compared to vehicle; data are plotted as group
mean SEM. Plasma exposure measured at 379 133 nM at 10 mpk dose.
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of the meta-series demonstrated a preference for C5 substitution
while highlighting difference in the effect of substitution on po-
tency elsewhere on the ring. Investigation of the SAR around the
hydrophobic left-hand side of the para-linked chromenones gave
similar trends in potency relative to that of the phthalazinone ser-
ies as highlighted by compounds 15 and 21 compared to 4 and 2.
Furthermore, 5-substituted, para-linked chromenones 15 and
19 were identified as potent B1 antagonists. These analogs gave
over eightfold increase in activity in an hB1 functional assay and
over fourfold increase in activity in a rabbit B1 functional assay
as well as similar or improved pharmacokinetic properties when
compared to unsubstituted chromenone 4. 5-Chlorochromenone
15 additionally proved efficacious in a rabbit carrageenan model
for inflammatory pain. Beneficial SAR discovered outside of the
fused 6,6-ring system of the phthalazinone core is expected to fur-
ther improve both potency and pharmacokinetic properties of
these compounds. The potential to exploit alternate chemical space
17. Dong, H.; Sun, H.; Magal, E.; Ding, X.; Kumar, G. N.; Chen, J. J.; Johnson, E. J.;
Manning, B. H. J. Neurosci. Methods 2008, 168, 76.