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

2232 R. P. Verma, C. Hansch / Bioorg. Med. Chem. 15 (2007) 2223–2268
R 1 (P1' substituent):
Major determinant of activity and selectivity
Small alkyl groups preferred for MMP-1 activity
Longer alkyl and phenylalkyl chains offer
selectivity over MMP-1 and MMP-7
Zinc-binding group:
Hydroxamic acid preferrred
Ra (α substituent):
Increases activity
Can be cyclized to R 2
HO NH
of the data, and not on the hypotheses, and is valid only
for the compound structures analogues to those used to
build the model. QSAR models can stand alone to augment
other graphical approaches or can be examined in
tandem with equations of a similar mechanistic genre to
establish their authenticity and reliability. 82 Potential
use of QSAR models for screening of chemical databases
or virtual libraries before their synthesis appears
equally attractive to chemical manufacturers, pharmaceutical
companies, and government agencies.
It is important to distinguish between SARs and
QSARs: SARs are occurring in the form of structural
features that include molecular substructures or fragment
counts related to the presence or absence of biological
activity; while QSARs are typically quantitative
in nature, producing categorical or continuous prediction
scales. 83
10.1. Review of QSAR studies on MMP inhibitors from
the literature
An attempt has been made to collect the QSAR data on
MMP inhibitors from the literature, resulting in a total
O
R 1
H
N
Ra O R2 Amide backbone:
O
R3 N
H
N-Methylation, Reverse amides
reduce activity
R 3 (P3' substituent):
Aromatic groups preferred
Charged/polar groups may
affect biliary excretion
R2 (P2' substituent):
Aromatic substituens preferred for in vitro activity
Cyclization to Ra or R3 Steric bulk close to amides is beneficial for oral bioavailability
Figure 14. Summary of the structure–activity relationships (SARs) for right-hand side MMP inhibitors. Reprinted with permission from Ref. 7.
Copyright 1999 American Chemical Society.
R 3 (P3 substituent):
Proline is preferred to all enzymes.
L-thioproline enhances activity of
MMP-2 and MMP-3
O
O N H
R 3
O
H
N
R 2
O
N
H
R 1
O
H
N OH
R 1 (P1 substituent):
Ala, Glu, Gly, Leu preferred.
L-stereochemistry and an extended
side chain will improve activity.
Glu provides significant cleavage by
MMP-7 and MMP-8 and negligible
by MMP-1, MMP-2, and MMP-9.
Val results in negligible cleavage
for all enzymes
Zinc-binding group:
Hydroxamic acid preferrred
R2 (P2 substituent):
Arg, Leu, Met, Phe preferred.
L-homophenylalanine enhances activity of MMP-2 and MMP-3.
Arg is preferred for MMP-2 selectivity and Met appears
to be good for MMP-7.
Figure 15. Summary of the structure–activity relationships (SARs) for
left-hand side MMP inhibitors. 7
number of 44 QSAR models that are shown in Table 5.
The descriptions about the physicochemical parameters,
used for the derivation of these QSAR models, are listed
in Table 6. The inhibition potency of various compound
series against MMP-1, -2, -3, -7, -8, -9, and -13 has been
found to be well correlated with a number of physicochemical
and structural parameters. The important
parameters for these correlations are hydrophobicity,
Kier’s first-order valence molecular connectivity index
( 1 v v ) of the molecule/substituent, electrotopological state
(E-state) indices (Si) of the atom (i = S or N), and polarizability
(Pol. or NVE). The most important of these is
hydrophobicity, which is one of the most important
determinants of inhibitory activity. Out of 44 QSAR,
18 contain a correlation between inhibitory activity
and hydrophobicity of the molecule/substituent. A negative
linear correlation is found in 14 equations (Eqs.
E2–E4, E12, E18, E25–E27, E33, E34, E36, E37, E39,
and E43), and the coefficient ranges from 0.062 (Eq.
E3) to 1.24 (Eq. E36). Less hydrophobic congeners
in these compound families might display enhanced
activity. A positive linear correlation is found in only
one equation (Eq. E11). This suggests that the activity
of this data set might be improved by increasing hydrophobicity
of the substituents at ortho and meta positions.
Parabolic correlations with hydrophobicity are
found in three equations (Eqs. E1, E13, and E28), which
reflect situations where activity declines with increasing
hydrophobicity and then changes direction and increases.
It may correspond to an allosteric reaction. 91–99
10.2. Evaluation of new QSAR on MMP inhibitors
10.2.1. Materials and methods. All the data have been
collected from the literature (see individual QSAR for
respective references). IC50 is the 50% inhibitory concentration
of a compound, which is expressed in molar concentration.
Similarly, K i is the inhibitory constant of a
compound and is also expressed in molar concentration.
log1/IC50 and log1/Ki are the dependent variables,
which define the biological parameter for QSAR equations.
Physicochemical descriptors are auto-loaded,
and multi-regression analyses (MRA) used to derive