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

2230 R. P. Verma, C. Hansch / Bioorg. Med. Chem. 15 (2007) 2223–2268
S1/2 site
S1/S2 site
HO
HN
X
O
Zn 2+
O
N P
O
OH
N
H
N
P R1 O O
R2 S1' pocket
S2'/S3' site
Figure 7. Structure–activity relationships (SARs) for phosphonamidebased
hydroxamic acids. Reprinted with permission from Ref. 71.
Copyright 2002 American Chemical Society.
The SAR study has shown that the ester group (R1)
seems to have little interaction with the S2 0 /S3 0 site of
MMPs, especially of MMP-1. The effects of the substituents
R2 attached to the phosphonamide are important.
Introduction of a long alkoxyalkyl chain at the para
position of the phenyl ring resulted in the significant decrease
of the inhibitory activity against MMP-1, while
the inhibitory activities of other enzymes were maintained
or increased. Thus, the R 2-substituents would
bind to the S1 0 pocket of the MMP enzymes, because
this pocket is deep for most MMP enzymes, but it is
short for MMP-1. On the other hand, bulky substituents
at the para position of the phenyl ring increased the
inhibitory activity for MMP-9. Insertion of an alkyl
chain between the phenyl ring and the phosphonamide
moiety resulted in a slight decrease of the inhibitory
activity for all enzymes, but the alkenyl chain dramatically
decreased the activity for MMP-1. Hydrogen bond
(in case of fluorine atom) or a tight bond of the hydroxa-
H N
Me
peptide backbone
S1' pocket
S2'/3' direction
Figure 6. Binding interaction of N-hydroxy-2(R)-[[(R)-methylphenylphosphinyl]-benzylamino]-4-methylpentanamide
in MMP enzyme.
Reprinted with permission from Ref. 71. Copyright 2002 American
Chemical Society.
P1' substituent: Crucial for potency
and selectivity. Aromatic substituents
are superior, especially R 2 = phenoxy
with the R-configuration at phosphorus.
Zinc-binding group:
A hydroxamic acid is
the superior group
HO
N
H
O
O
R 1
R 2
X
P
N
P1 substituent (only phosphonamides):
Both straight chain and branched alkyl
substituents with R-configuration are tolerated.
Potency for six-memberd ring increases upto
50 times, less for larger rings.
mate to the zinc ion and the p-methoxyphenyl moiety in
the S1 0 pocket have been mentioned to be obligatory.
The oxygen atom of the phosphonamide was positioned
at the hydrogen bond distance with the main chain of
the Leu-164 and Ala-165. Replacement of 1,2,3,4-tetrahydroisoquinoline
ring with other heterocycles provided
insight into the structural requirements of the S1/S2
binding site. Regarding the SAR for the X moiety,
reduction of the ring size resulted in a significant
decrease of the inhibitory activity against all enzymes.
Subsequent modeling work strongly supported the presence
of R-isomer at the phosphorus center. 71
9.1.2. Cyclophosphinamide and cyclophosphonamidebased
hydroxamic acids. An overview of the structure–
activity relationships for cyclophosphinamide and
cyclophosphonamide-based hydroxamic acids has been
shown in Figure 8. These two series of MMP inhibitors
were found equally potent in vitro but their SARs were
slightly different. The modeling-based binding mode
for these two series of MMP inhibitors is shown in
Figure 9. 72
9.1.3. Sulfonamide hydroxamates. The development of
first orally available broad-spectrum inhibitor from this
class of compounds is CGS 27023A. The key structure
of this inhibitor is the isopropyl substituent, which slows
down metabolism of the adjacent hydroxamic acid and
the basic 3-pyridyl substituent that may aid partitioning
X= O: phosphonamides
X = CH 2: phosphinamides
n
X = O, n = 1: Seven-membered rings
are most potent
X = CH 2, n = 0: Unsaturated
six-membered rings are most potent
Only phosphinamides (X = CH 2)
were optionally unsaturated.
Unsaturation increases potency.
Figure 8. Structure–activity relationships (SARs) for cyclophosphonamide and cyclophosphinamide-based hydroxamic acids. Reprinted with
permission from Ref. 72. Copyright 2003 Elsevier.
O
H
N
HO
O
Zn
O
Ala 165 Leu164
N
H
HN
O
P
N X
O
X = O: phosphonamides
X = CH 2: phosphinamides
S2'/S3' site
(Asn 162, Val 163)
S1' pocket
Figure 9. Binding mode of cyclophosphonamide and cyclophosphinamide-based
hydroxamic acids in MMP-3. Reprinted with permission
from Ref. 72. Copyright 2003 Elsevier.