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

2224 R. P. Verma, C. Hansch / Bioorg. Med. Chem. 15 (2007) 2223–2268
9.2.3. Biphenylsulfonamide carboxylic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2231
9.3. Summary of the structure–activity relationships (SARs). . . . . . . . . . . . . . . . . . . . . . . . . 2231
10. Quantitative structure–activity relationships (QSARs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2231
10.1. Review of QSAR studies on MMP inhibitors from the literature . . . . . . . . . . . . . . . . . . 2232
10.2. Evaluation of new QSAR on MMP inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2232
10.2.1. Materials and methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2232
10.2.2. Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2238
10.2.3. Validation of QSAR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2260
10.2.4. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2260
11. MMP inhibitors in clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2263
12. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2263
References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2265
1. Introduction
Matrix metalloproteinases (MMPs) are a large family of
calcium-dependent zinc-containing endopeptidases,
which are responsible for the tissue remodeling and degradation
of the extracellular matrix (ECM), including
collagens, elastins, gelatin, matrix glycoproteins, and
proteoglycan. MMPs are usually minimally expressed
in normal physiological conditions and thus homeostasis
is maintained. However, MMPs are regulated by hormones,
growth factors, and cytokines, and are involved
in ovarian functions. Endogenous MMP inhibitors
(MMPIs) and tissue inhibitors of MMPs (TIMPs) strictly
control these enzymes. Over-expression of MMPs
results in an imbalance between the activity of MMPs
and TIMPs that can lead to a variety of pathological
disorders. 1–5 A list of physiological and pathological
processes for which MMPs have been implicated is
shown in Table 1. 5,6 The earliest descriptions of MMPs
were in 1949 as depolymerizing enzymes which, it was
proposed, could facilitate tumor growth by making con-
Table 1. Involvement of MMPs in physiological and pathological
processes
Physiological
Pathological processes
processes
Angiogenesis Arthritis Multiple sclerosis
Apoptosis Alzheimer’s disease Nephritis
Blastocyst
Atherosclerosis Neurological
implantation
disease
Bone remodeling Breakdown of Osteoarthritis
blood–brain barrier (OA)
Cervical dilation Cancer Periodontal
disease
Embryonic
Cardiovascular Rheumatoid
development disease
Endometrial cycling Central nervous
system disorders
Skin ulceration
Hair follicle cycling Corneal ulceration Sorby’s fundus
disease
Immune response Emphysema Vascular disease
Inflammation Fibrotic lung disease
Nerve growth Gastric ulcer
Organ morphogenesis Guillian-Barre disease
Ovulation Liver cirrhosis
Postpartum uterine
involution
Liver fibrosis
Wound healing Metastasis
nective tissue stroma, including that of small blood vessels,
more fluid. About after 13 years, the first vertebrate
MMP, collagenase, was isolated and characterized as
the enzyme responsible for the resorption by tadpole
tail. During the next 20 years, several mammalian
enzymes were partially purified, but it was not until
1985 that the field really developed when structural
homologies became apparent, allowing many new members
to be identified through the techniques of molecular
biology. 7 In a recent work, it was concluded that smoking
alters the levels of matrix metalloproteinases in skin
tissue, serum, and saliva, which may affect the turnover
of extracellular matrix (ECM) of skin. 8
Matrix metalloproteinases are excreted by a variety of
connective tissue and pro-inflammatory cells including
fibroblasts, osteoblasts, endothelial cells, macrophages,
neutrophils, and lymphocytes. These enzymes are
expressed as zymogens, which are subsequently processed
by other proteolytic enzymes (such as serine proteases,
furin, plasmin, and others) to generate the active
forms. Under normal physiological conditions, the proteolytic
activity of the MMPs is controlled at any of the
following three known stages: activation of the zymogens,
transcription, and inhibition of the active forms
by various tissue inhibitors of MMPs (TIMPs). In pathological
conditions this equilibrium is shifted toward increased
MMP activity leading to tissue degradation. 9,10
MMPs have now been considered as a promising target
for cancer therapy and a large number of synthetic and
natural MMP inhibitors (MMPIs) have been identified
as cytostatic and anti-angiogenic agents, and have begun
to undergo clinical trials in view of their specific implication
in malignant tissues. Although preclinical studies
were compelling to encourage several clinical trials, the
past years have seen a consistent number of disappointing
results and/or limited success. The critical
examination of previous results has prompted serious
re-evaluation of MMP-inhibition strategies focusing
the attention of future research on the identification of
specific MMP targets in tumors at different stages of tumor
progression, both in order to improve efficacy and
to reduce the side-effect profile. 11,12
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