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

2246 R. P. Verma, C. Hansch / Bioorg. Med. Chem. 15 (2007) 2223–2268
Y
X
O
H
N
XIII
log 1=IC50 ¼ 0:35ð 0:16ÞClogP 3:63ð 0:68ÞI Y
þ 7:61ð 0:60Þ; ð13Þ
n =16, r 2 = 0.919, s = 0.471, q 2 = 0.869, Q = 2.036,
F = 73.747.
Positive ClogP suggests that highly hydrophobic P1 0
modified phenylalanine analogues (XIII) would be more
active. The indicator variable (I Y) applies to those compounds,
which have Y = COOH. The negative coefficient
of the indicator variable indicates that the
presence of CONHOH group at Y-position will improve
the activity. As the large coefficient of indicator variable
(IY) suggests that compounds with Y = COOH and
CONHOH may act by different mechanism.
Inhibition of MMP-2 by sulfonamide derivatives (XIV).
Data obtained from Martin et al. 123 (Table 20).
HO NH
O
R1 N
O S O
R2 XIV
O
R
O
N
H
X
log 1=IC50 ¼ 0:43ð 0:12ÞClogP 0:43ð 0:32ÞI R
þ 1:09ð 0:34ÞI R1 þ 4:75ð 0:35Þ; ð14Þ
n = 20, r 2 = 0.893, s = 0.270, q 2 = 0.821, Q = 3.500,
F = 44.511.
QSAR 14 is an unusual equation. Despite rather wide
variation in substituents at three positions, there is no
outlier. ClogP is the most significant term, followed
by two indicator variables (IR) and (IR1). The indicator
variable (IR) takes the value of 1 for the presence of the
isopropyl group and 0 for cyclopentyl group in the
R-position. Similarly, the indicator variable (IR1) takes
the value of 1 for the presence of the methyl group
and 0 for others in R 1-position. The negative coefficient
of IR indicates that the presence of cyclopentyl group at
R-position will improve the activity. The positive coefficient
of I R1 indicates that CH 3 group is preferred over
the other substituents at R1-position.
Inhibition of MMP-2 by succinyl hydroxamates and their
carboxylic analogues (XV). Data obtained from Fray
et al. 124 (Table 21).
Table 20. Biological, physicochemical, and structural parameters used to derive QSAR equations 14 and 20 for the inhibition of MMP-2 and
MMP-3, respectively, by sulfonamide derivatives (XIV)
No. R X R1 R2 log1/IC50 (Eq. 14) log1/IC50 (Eq. 20) ClogP IR IR1
Obsd. Pred. D Obsd. Pred. D
1 Isopropyl Piperidinyl Methyl Methyl 5.00 5.46 0.46 5.40 5.77 0.37 0.13 1 1
2 Isopropyl Piperidinyl Methyl Ethyl 5.70 5.69 0.01 5.70 6.03 0.33 0.65 1 1
3 Isopropyl Piperidinyl Methyl Ph(4-OMe) 6.22 6.27 0.05 6.40 6.70 0.30 2.01 1 1
4 Isopropyl Piperidinyl Methyl Dansyl 7.10 6.87 0.23 7.22 7.39 0.17 3.41 1 1
5 Isopropyl N(Me)2 Methyl Methyl 5.70 5.43 0.27 — — — 0.04 1 1
6 Cyclopentyl Piperidinyl Methyl Methyl 6.05 6.16 0.11 6.70 6.08 0.62 0.76 0 1
7 Cyclopentyl Piperidinyl Methyl Ethyl 6.22 6.39 0.17 6.40 6.34 0.05 1.29 0 1
8 Cyclopentyl Piperidinyl Methyl Ph(4-OMe) 7.22 6.97 0.25 7.22 7.01 0.21 2.64 0 1
9 Cyclopentyl Piperidinyl Methyl Dansyl 7.70 7.56 0.14 8.15 7.70 0.45 4.04 0 1
10 Cyclopentyl Piperidinyl Methyl Naphthalyl 7.30 7.40 0.10 7.30 7.51 0.21 3.65 0 1
11 Cyclopentyl Piperidinyl n-Propyl Methyl 5.52 5.53 0.01 5.22 5.33 0.11 1.82 0 0
12 Cyclopentyl Piperidinyl Cyclopentyl Methyl 5.52 5.71 0.19 5.00 5.54 0.54 2.23 0 0
13 Cyclopentyl Piperidinyl Cyclopropyl Methyl 5.70 5.23 0.47 5.70 4.98 0.72 1.11 0 0
14 Cyclopentyl Piperidinyl Isopropyl Methyl 5.15 5.44 0.29 5.16 5.22 0.07 1.60 0 0
15 Cyclopentyl Piperidinyl Methyl Isopropyl 6.40 6.52 0.12 6.52 6.50 0.02 1.60 0 1
16 Cyclopentyl Piperidinyl Methyl Ph(4-Cl) 7.00 7.20 0.20 7.52 7.28 0.24 3.18 0 1
17 Cyclopentyl Piperidinyl Methyl N(Me) 2 6.52 6.15 0.37 6.40 6.07 0.33 0.74 0 1
18 Cyclopentyl Piperidinyl Methyl CF3 6.30 6.64 0.34 6.10 6.63 0.53 1.87 0 1
19 Cyclopentyl Morpholinyl Methyl Methyl 6.40 6.17 0.23 6.10 6.09 0.01 0.77 0 1
20 Cyclopentyl Morpholinyl Methyl Ph(4-OMe) 7.02 6.97 0.05 7.00 7.02 0.02 2.65 0 1
X
O
O
H
N
XV
O
Y
N
H