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

2258 R. P. Verma, C. Hansch / Bioorg. Med. Chem. 15 (2007) 2223–2268
Table 40. Biological, physicochemical, and structural parameters used to derive QSAR equation 42 for the inhibition of MMP-13 by diazepinehydroxamates
(XXXII)
No. X Y log1/IC50 (Eq. 42) CpYI Obsd. Pred. D
1 CH3CH2C6H5 7.19 7.35 0.16 2.27 0
2 CH3COC6H5 8.66 8.80 0.14 1.06 1
3 C6H5COC6H5 8.89 8.80 0.09 1.06 1
4 CH3COC6H4-4-OCF3 8.21 8.34 0.13 2.39 1
5 CH3COC6H4-2-C6H5 8.34 8.15 0.19 2.95 1
6
7
CH3COCH2NHOCOC(CH3)3 7.80 7.96 0.16 0.52 0
a
CH3 COCH2NH2 Æ HCl 7.34 8.43 1.09 0.85 0
8 CH3COC(CH3) 3 7.96 7.92 0.04 0.63 0
9 CH3COOC(CH3)3 7.59 7.46 0.13 1.97 0
10 CH3 H Æ HCl 8.29 8.14 0.15 0.00 0
11 CH3 CONHC6H5 7.77 7.76 0.01 1.11 0
a
Not included in the derivation of QSAR 42.
log 1=IC50 ¼ 0:35ð 0:15ÞCpY þ 1:03ð 0:27ÞI
þ 8:14ð 0:22Þ; ð42Þ
n =10, r 2 = 0.925, s = 0.159, q 2 = 0.824, Q = 6.050,
F = 43.167.
Cp Y is the calculated hydrophobic parameter for Y-substituents.
The indicator variable (I) takes the value of 1
for the presence of COPh or its derivatives and 0 for the
others in Y-position. The positive coefficient of I
indicates that the presence of COPh or its derivatives
at Y-position will improve the activity as observed in
Table 40.
Inhibition of MMP-13 by carboxylic acid derivatives
(XXV). Data obtained from Pikul et al. 134 (Table 33).
log 1=IC50 ¼ 2:67ð 1:42ÞCpX
þ 2:55ð 0:57ÞCMRX
þ 0:98ð 0:55ÞCMRY
þ 4:21ð 2:65Þ; ð43Þ
n =15, r 2 = 0.906, s = 0.341, q 2 = 0.799, Q = 2.792,
F = 35.341.
Cp X is the calculated hydrophobicity of the X-substituents,
whereas CMRX and CMRY are the molar refractivities
of X- and Y-substituents, respectively. No term
appears for Z-substituents.
Inhibition of MMP-13 by amide-substituted piperazine
derivatives (XXXIII). Data obtained from Cheng
et al. 9 (Table 41).
O
O S
O
HO N
N
H
N
O
X
XXXIII
OCH 3
log 1=IC50 ¼ 0:62ð 0:21ÞClogP
0:72ð 0:18ÞCMR
þ 15:30ð 1:73Þ; ð44Þ
n = 10, r 2 = 0.925, s = 0.157, q 2 = 0.842, Q = 6.127,
F = 43.167.
Table 41. Biological and physicochemical parameters used to derive QSAR equation 44 for the inhibition of MMP-13 by amide-substituted
piperazine derivatives (XXXIII)
No. X log1/IC50 (Eq. 44) ClogP CMR
Obsd. Pred. D
1 CH3 9.00 9.07 0.07 0.15 8.58
2 n-C5H11 8.77 9.04 0.27 1.96 10.43
3 c-C6H11 8.82 8.78 0.04 1.88 10.72
4 CH(OH)CH(Me)2 9.00 8.85 0.15 1.30 10.12
5 CH2OC6H5 8.68 8.50 0.18 2.03 11.24
6 C6H5 8.52 8.56 0.04 1.40 10.63
7 Thiophen-2-yl 8.72 8.56 0.16 1.18 10.43
8 Furan-2-yl 8.60 8.61 0.01 0.58 9.84
9 5-CH3-C2N2S-4-yl 7.68 7.71 0.03 0.15 10.48
10
11
3-C6H5-5-CH3-Isoxazol-4-yl 7.57 7.67 0.10 2.26 12.60
a
C6H4-4-C6H5 9.05 7.92 1.13 3.29 13.14
a
Not included in the derivation of QSAR 44.