996
L. Xing et al. / Bioorg. Med. Chem. Lett. 21 (2011) 993–996
Table 2
current study we demonstrated that the combination of computer
modeling design and parallel medicinal chemistry could rapidly
explore the interesting binding pocket space and develop struc-
tural–activity and structure–property relationships. In particular,
the substitution on phenyl group at position 8 of benzopyran
COX-2 lead SD-8381 preferred hydrophobic groups, but disfavored
hydrogen bond bearing polar functions, to retain high binding
affinity and selectivity against COX-2. Reduction of metabolic sta-
bility in phase I metabolism was achieved by installing lipophilic
moieties on the 8-phenyl off benzopyran. A few analogs such as
6l and 6p were carried on for further investigation in vivo. New
lead compounds had emerged from our efforts to advance the
COX2 drug discovery program.
Comparison of experimental and calculated relative binding free energies (kcal/mol)
A?B
Calculated
DDGbinding
D
Gaq
1.5454
1.1312
D
GCOX2
Calcd
Exptla
6i?6h
6j?6h
6j?6i
0.4513
1.1578
À1.0941
0.0266
<À3.718
1.096
À0.8280
À0.1158
0.7122
2.5975
>5.014
0.356
6k?6h
6k?6i
6k?6j
6k?6f
6k?6c
6l?6k
6l?6e
6m?6l
6n?6m
1.7415
4.3390
0.3697
0.9269
À0.8550
À0.4958
À11.3169
À9.9471
À0.4782
À5.9378
À6.6389
5.9868
À1.2247
À1.4227
À0.7867
0.8474
>4.075
À0.9393
2.085
À10.5302
À10.7945
À0.3905
À6.4125
À0.076
1.701
0.1617
2.606
À0.0877
0.4747
À5.9313
3.4597
À0.895
2.5271
0.2270
References and notes
D
Gaq is the entropy change in the aqueous phase upon desolvation, and
DGCOX2 is
the enthalpy change upon binding to COX2 protein.
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