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

2242 R. P. Verma, C. Hansch / Bioorg. Med. Chem. 15 (2007) 2223–2268
Table 12. Biological, physicochemical, and structural parameters used to derive QSAR equation 6 for the inhibition of MMP-1 by 3-OH-3methylpipecolic
hydroxamates (VI)
No. X log1/IC50 (Eq. 6) ClogP CMR IX Obsd. Pred. D
1 2-Fluorophenyl 6.74 6.66 0.08 2.55 10.85 0
2 3-Fluorophenyl 6.47 6.66 0.19 2.55 10.85 0
3 4-Fluorophenyl 6.38 6.66 0.28 2.55 10.85 0
4 2-Chlorophenyl 6.57 6.52 0.05 3.12 11.33 0
5 a
3-Chlorophenyl 6.07 6.52 0.45 3.12 11.33 0
6 2-Methylphenyl 6.51 6.33 0.18 2.85 11.30 0
7 2-Methoxyphenyl 5.59 5.65 0.06 2.32 11.45 0
8 2-Cyanophenyl 5.57 5.54 0.03 1.98 11.32 0
9 a
2-Methyl-3-fluorophenyl 5.89 6.43 0.54 3.00 11.32 0
10 2-Methyl-4-fluorophenyl 6.66 6.43 0.23 3.00 11.32 0
11 2-Methyl-5-fluorophenyl 6.22 6.43 0.21 3.00 11.32 0
12 2-Chloro-4-fluorophenyl 6.51 6.63 0.12 3.26 11.34 0
13 2-Fluoro-4-chlorophenyl 6.92 6.63 0.29 3.26 11.34 0
14 Pyridin-4-yl 6.72 6.34 0.38 0.91 10.63 1
15 Pyrazinyl 5.80 5.78 0.02 0.05 10.42 1
16 4-Isoquinolinyl 5.11 5.10 0.01 2.08 12.31 1
17 a
4-Quinolinyl 6.92 5.28 1.64 2.29 12.31 1
18 2-Chloro-4-pyridinyl 6.28 6.38 0.10 1.70 11.12 1
19 2-Methyl-3-pyridinyl 5.80 6.11 0.31 1.36 11.09 1
a Not included in the derivation of QSAR 6.
Table 13. Biological and physicochemical parameters used to derive QSAR equation 7 for the inhibition of MMP-1 by phosphinic acid derivatives
(VII)
No. X log1/IC50 (Eq. 7) CMRX-4
Obsd. Pred. D
1 a
4-CH2C6H5 6.57 5.68 0.89 2.98
2 H 4.82 5.05 0.23 0
3 2-C6H5 4.96 5.05 0.09 0
4 3-C6H5 5.29 5.05 0.24 0
5 4-C6H5 5.66 5.58 0.08 2.51
6 3-CH2CH2C6H5 5.13 5.05 0.08 0
7 4-CH2CH(Me) 2 5.35 5.41 0.06 1.72
8 4-CH2C6H11 5.72 5.70 0.02 3.07
9 4-SO2C6H5 5.77 5.77 0.00 3.38
10 4-OC6H5 5.55 5.61 0.06 2.66
a Not included in the derivation of QSAR 7.
Inhibition of MMP-1 by sulfonylated amino acid
hydroxamates (VIII). Data obtained from Scozzafava
and Supuran 117 (Table 14).
HO
NH Z
O
N
O S
Y
X O
VIII
log 1=Ki ¼ 0:42ð 0:07ÞCMR 0:17ð 0:06ÞB5X
1:05ð 0:20ÞLY 1:97ð 0:59ÞB1Y
þ 15:24ð 1:79Þ; ð8Þ
n =31, r 2 = 0.884, s = 0.177, q 2 = 0.838, Q = 5.311,
F = 49.534. ClogP versus CMR: r = 0.858; ClogP versus
B5X: r = 0.609; ClogP versus LY: r = 0.200. ClogP
versus B1Y: r = 0.442; CMR versus B5X: r = 0.265;
CMR versus LY: r = 0.482. CMR versus B1Y: r =
0.059; B5X versus LY: r = 0.035; B5X versus B1Y:
r = 0.062. L Y versus B1 Y: r = 0.207.
The most important term is the molar refractivity of the
whole molecule (CMR), followed by sterimol parameters
of X- and Y-substituents (B5X, LY, and B1Y). B5X
is the sterimol parameter for the largest width of the
X-substituent, while B1Y is for the smallest width of
the Y-substituent, pointing to the steric effects at respective
positions. LY is the sterimol parameter for the
length of Y-substituent. With respect to QSAR 8, itis
important to note that there is a high mutual correlation
between Clog P and CMR (r = 0.858). By considering
ClogP in place of CMR, we can derive QSAR 8a.
log 1=Ki ¼ 0:61ð 0:19ÞClogP 0:35ð 0:14ÞB5X
0:28ð 0:27ÞLY 3:37ð 1:17ÞB1Y
þ 14:94ð 2:97Þ; ð8aÞ