B. Baruah et al. / Bioorg. Med. Chem. Lett. 14 (2004) 445–448
447
Scheme 2.
mogenic assay based on oxidation of N,N,N,N-tetra-
methyl-p-phenylenediamine (TMPD) during the reduc-
tion of PGG2 to PGH2. The assay mixture (1000 mL)
contained 100 mM Tris pH 8.0, 3 mM EDTA, 15 mM
hematin, 150 units enzyme and 8% DMSO. The mix-
ture was incubated at 25 ꢀC for 15 min before initiation
of enzyme reaction in presence of compound/vehicle.
The reaction was initiated by the addition of 100 mM
arachidonic acid and 120 mM TMPD. The enzyme
activity was measured by estimation of the initial velo-
city of TMPD oxidation over the first 25 s of the reac-
tion followed from the increased in absorbancy at
603 nm. The IC50 values were calculated using non-lin-
ear regression analysis of percentage inhibition.
Acknowledgements
The authors thank analytical department, Dr. A. Ven-
kateswarlu and Dr. R. Rajagopalan for their support
and discussions.
References and notes
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As can be readily understood from Table 1, in the dia-
ryl-1-ethanone series 1, COX-2 selectivity mainly
depends on the substituent on both the aryl ring as well
as on the heterocycles. When the sulfonyl or sulfanyl
group is in 1-aryl ring, selectivity decreases though it
inhibits both COX-1 and COX-2. But when these
groups are shifted to 2-aryl ring, the selectivity changes
dramatically. The selectivity also depends on the sub-
stituted heterocycles. Thus, in this series, we were able
to get selective inhibitors like 1c (IC50=500 mM for
COX-1 and 2.1 mM for COX-2) and 1i (IC50=50 mM for
COX-1 and 0.5 mM for COX-2).
In series 2, when R, R1, R2 are only H, the compounds
are more COX-1 selective whereas when R2 is replaced
by NO2 and R1 by sulfonamide group, the selectivity is
more towards COX-2. By synthesizing a limited number
of compounds, we were able to identify few highly
active and selective COX-2 inhibitors like 2d
(IC50=4.7 mM for COX-1 and 0.24 mM for COX-2) and
2f (IC50=5.0 mM for COX-1 and 0.55 mM for COX-2).
All the four compounds were showing activity in the
range of 25–45% in Carrageenan induced rat paw
model at 30 mg/Kg.11
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K.; Parimal, M.; Seshagiri Rao, C.; Koteswar Rao, Y.
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In conclusion, 1,2-diaryl-1-ethanones 1c and 1i and
pyrazolo [4,3-c] quinoline-4-one 2d and 2f were identi-
fied as selective COX-2 inhibitors. The results presented
here indicate that the two novel series may serve as
alternative pharmacophores.