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VOL. 73 (3), 703-746, 2007 ARE ADRENOMEDULLIN POSITIVE MODULATORS NOVEL...

INTRODUCTION

Matrix Metalloproteinases Classification

Matrix metalloproteinases (MMPs), also called matrixins, are a
family of structurally related zinc-containing enzymes that mediate
the breakdown of connective tissue and are therefore targets for
therapeutic inhibitors in many inflammatory, malignant, and
degenerative diseases (3).

The mammalian MMP family is now known to include at
least 24 enzymes. The most studied are three collagenases:
interstitial collagenase (MMP-1), neutrophil collagenase (MMP-8),
and collagenase-3 (MMP-13). These enzymes can degrade the
fibrillar collagens, which are generally resistant to proteolysis.
The MMP family also includes two type IV collagenases, termed
gelatinase A (MMP-2) and gelatinase B (MMP-9), which can
degrade type IV collagen of basal laminae, as well as other non
helical collagen domains and proteins, such as fibronectin and
laminin. Stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10)
degrade various proteoglycan components of the extracellular matrix
as well as fibronectin and laminin.

Several subsites have been described (S1, S2, S3, S1’, S2’, and
S3’) being responsible for different roles affecting activity
and selectivity, depending on the MMP considered (4). These
requirements can be satisfied by a variety of different structural
classes of MMP inhibitors (MMPIs), which have been discovered by
a number of methods, including structure-based design (5, 6) and
combinatorial chemistry (7).

Proteolytic Reaction Mechanism

The proteolytic reaction of MMPs has been rationalized on the
basis of structural information (Figure 1) (8). It has been proposed
that the scissile amide carbonyl coordinates to the active site
Zn2+ ion. This carbonyl is attacked by a water molecule that is
simultaneously hydrogen bonded to a conserved glutamic acid

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