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

2252 R. P. Verma, C. Hansch / Bioorg. Med. Chem. 15 (2007) 2223–2268
Table 29. Biological and physicochemical parameters used to derive QSAR equation 25 for the inhibition of MMP-3 by thiazepine derivatives (XXII)
No. X Y log1/IC50 (Eq. 25) r +
Obsd. Pred. D
1 a
S 4-OCH3 9.15 8.27 0.88 0.78
2
3
SO24-OCH3 8.16 8.27 0.11 0.78
a
S 4-Br 8.00 6.90 1.10 0.15
4 SO24-Br 7.05 6.90 0.15 0.15
5 S 2-CH3,4-Br 7.06 7.36 0.30 0.16
6 S 4-OC4H9 8.18 8.32 0.14 0.81
7 SO24-OC4H9 8.57 8.32 0.25 0.81
8 S 4-C3H7 7.34 7.55 0.21 0.29
9 S 4-C5H11 7.60 7.55 0.05 0.29
10 S 4-O(CH2)2OCH3 7.77 7.55 0.22 0.29
11 S 4-OC6H5 7.96 7.86 0.10 0.50
a Not included in the derivation of QSAR 25.
a hydrogen bond between Leu-164 and the sulfonamide
oxygen may develop.
10.2.2.4. MMP-7 inhibitors. Inhibition of MMP-7 by
hydroxamate derivatives containing hydantoin moiety
(XXIII). Data obtained from Natchus et al. 132 (Table
30).
HO
N
H
O
O
O
O S
N
X
N
XXIII
O
N
Y
log 1=IC50 ¼ 0:59ð 0:11ÞClogP
Z
1:94ð 0:56ÞMgVol
þ 11:58ð 1:78Þ; ð26Þ
n = 13, r 2 = 0.937, s = 0.124, q 2 = 0.908, Q = 7.806,
F = 74.365.
Inhibition of MMP-7 by tetrahydroisoquinoline-based sulfonamide
hydroxamates (XXIV). Data obtained from
Ma et al. 133 (Table 31).
R 1O
R
HO
N
H
N
S
O O
O
XXIV
log 1=IC50 ¼ 0:58ð 0:26Þr þ
Y þ 5:03ð 0:14Þ; ð27Þ
n =7, r 2 = 0.873, s = 0.145, q 2 = 0.758, Q = 6.441,
F = 34.370.
Negative coefficient of rþ Y indicates that electron-releasing
Y-group may enhance the inhibitory potency of the
molecules.
Table 30. Biological and physicochemical parameters used to derive QSAR equation 26 for the inhibition of MMP-7 by hydroxamate derivatives
containing hydantoin moiety (XXIII)
No. X Y Z log1/IC50 (Eq. 26) ClogP MgVol
Obsd. Pred. D
1
2
H CH3OCH3 5.74 5.71 0.03 0.92 2.75
a
H CH3OC2H5 5.12 5.74 0.62 0.39 2.89
3 H CH3O(CH2) 2CH3 5.59 5.78 0.19 0.14 3.03
4 H CH3O(CH2)3CH3 5.80 5.82 0.02 0.67 3.18
5 H CH3OCH2CH(CH)2 5.64 5.47 0.17 0.43 3.02
6
7
H CH3O(CH2) 2OCH3 5.04 4.98 0.06 1.03 3.09
a
H CH3OC6H5 6.51 5.93 0.58 1.01 3.22
8 H CH3O-4-Pyridyl 5.13 5.13 0.00 0.48 3.18
9 SCH3 H O(CH2)3CH3 6.07 6.05 0.02 1.61 3.34
10 (CH3) 2 H O(CH2) 3CH3 6.35 6.34 0.01 1.83 3.26
11 H CH2CH@CH2 O(CH2)2CH3 5.59 5.77 0.18 0.92 3.27
12 H CH2CH@CH2 O(CH2)3CH3 6.00 5.81 0.19 1.44 3.41
13 H CH2CH@CH2 O(CH2)2OCH3 4.96 4.97 0.01 0.25 3.33
14 H CH2CH2CH3 O(CH2) 3CH3 5.92 5.89 0.03 1.73 3.46
15 H CH2CH2CH3 O(CH2)2OCH3 4.96 5.06 0.10 0.03 3.38
a Not included in the derivation of QSAR 26.
Y