Matrix metalloproteinases (MMPs): Chemical–biological functions ...

2256 R. P. Verma, C. Hansch / Bioorg. Med. Chem. 15 (2007) 2223–2268
Table 36. Biological and physicochemical parameters used to derive QSAR equation 35 for the inhibition of MMP-9 by biphenylsulfonamide
derivatives (XXVIII)
No. X log1/IC50 (Eq. 35) MRX-4 r
Obsd. Pred. D
1 H 4.59 4.47 0.12 0.10 0.00
2 4-F 4.19 4.39 0.20 0.09 0.06
3 4-Br 5.10 5.25 0.15 0.89 0.23
4 3-Br 4.00 4.02 0.02 0.10 0.39
5 4-Cl 4.80 4.87 0.07 0.60 0.23
6 2-F,4-Br 5.31 5.19 0.12 0.89 0.29
7 4-Me 5.41 5.29 0.12 0.56 0.17
8 4-OMe 5.66 5.70 0.04 0.79 0.27
9 a
4-NH2 4.70 5.82 1.12 0.54 0.66
10 4-CF3 4.70 4.38 0.32 0.50 0.54
11 4-CN 4.23 4.42 0.19 0.63 0.66
12 4-CHO 4.77 4.77 0.00 0.69 0.42
13 4-NO2 4.42 4.42 0.00 0.74 0.78
a
Not included in the derivation of QSAR 35.
the substituents. Negative coefficient of r indicates that
electron-releasing X-group may enhance the inhibitory
potency of the molecules.
Inhibition of MMP-9 by spiro-barbiturates (XXIX).
Data obtained from Kim et al. 75 (Table 37).
R
O
N
HN
O
N H
O
O
XXIX
log 1=Ki ¼ 1:19ð 0:46ÞB1X þ 7:07ð 0:66Þ; ð36Þ
n =6, r 2 = 0.928, s = 0.126, q 2 = 0.837, Q = 7.643,
F = 51.556. pX versus B1X: r = 0.078.
O
X
B1X is the sterimol parameter for X-substituents, which
is the measure of minimum width suggesting a positive
effect on the inhibition.
10.2.2.7. MMP-12 inhibitors. Inhibition of MMP-12
by phosphinic acids (XXX). Data obtained from Reiter
et al. 138 (Table 38).
Table 37. Biological and physicochemical parameters used to derive QSAR equations 36 and 40 for the inhibition of MMP-9 and MMP-13,
respectively, by spiro-barbiturates (XXIX)
No. R X log1/Ki (Eq. 36) log1/Ki (Eq. 40) B1X pX Obsd. Pred. D Obsd. Pred. D
1 H H 8.33 8.26 0.07 8.33 8.49 0.16 1.00 0.00
2 C2H5H 8.14 8.26 0.12 8.39 8.49 0.10 1.00 0.00
3 H Cl 9.14 9.21 0.07 9.02 8.84 0.18 1.80 0.71
4 H COOCH3 8.92 9.02 0.10 8.38 8.49 0.11 1.64 0.01
5 H COOH 9.14 8.97 0.17 8.57 8.34 0.23 1.60 0.32
6 H OC6H58.72 8.68 0.04 9.48 9.51 0.03 1.35 2.08
Table 38. Biological and physicochemical parameters used to derive QSAR equation 37 for the inhibition of MMP-12 by phosphinic acids (XXX)
No. X Y log1/IC50 (Eq. 37) ClogP
Obsd. Pred. D
1 H CH2C6H58.09 8.21 0.12 4.79
2 Cl CH2C6H58.77 8.60 0.17 5.50
3 H CH2C6H4-2-OCH3 8.40 8.16 0.24 4.71
4 Cl CH2C6H4-2-OCH3 8.30 8.56 0.26 5.42
5 H H 7.03 7.06 0.03 2.72
Y
O
P
OH
XXX
X
O
H
N
O
N
H