A Potent, Selective Inhibitor of Matrix Metalloproteinase-3 for the Topical Treatment of Chronic Dermal Ulcers

Abstract

The pathology of chronic dermal ulcers is characterized by excessive proteolytic activity which degrades extracellular matrix (required for cell migration) and growth factors and their receptors. The overexpression of MMP-3 (stromelysin-1) and MMP-13 (collagenase-3) is associated with nonhealing wounds, whereas active MMPs-1, -2, -9, and -14 are required for normal wound healing to occur. We describe the synthesis and enzyme inhibition profile of (3R)-3-[([(1S)-2,2-dimethyl-1-(([(1S)-2-methoxy-1-phenylethyl]amino)carbonyl)propyl]amino)carbonyl]-6-(3-methyl-4-phenylphenyl)hexanoic acid (UK-370,106, 7), which is a potent inhibitor of MMP-3 (IC(50) = 23 nM) with >1200-fold weaker potency vs MMP-1, -2, -9, and -14. MMP-13, which may also contribute to the pathology of chronic wounds, was inhibited about 100-fold less potently by compound 7. Compound 7 potently inhibited cleavage of [(3)H]-fibronectin by MMP-3 (IC(50) = 320 nM) but not cleavage of [(3)H]-gelatin by either MMP-2 or -9 (up to 100 microM). Compound 7 had little effect, at MMP-3 selective concentrations, on keratinocyte migration over a collagen matrix in vitro, which is a model of the re-epithelialization process. Following iv (rat) or topical administration to dermal wounds (rabbit), compound 7 was cleared rapidly (t(1/2) = 23 min) from plasma, but slowly (t(1/2) approximately 3 days) from dermal tissue. In a model of chronic dermal ulcers, topical administration of compound 7 for 6 days substantially inhibited MMP-3 ex vivo. These data suggest compound 7 is sufficiently potent to inhibit MMP-3-mediated matrix degradation while leaving unaffected cellular migration mediated by MMPs 1, 2, and 9. These properties make compound 7 a suitable candidate for progression to clinical trials in human chronic dermal wounds, such as venous ulcers.

Physiology and pathophysiology of matrix metalloproteases

“…MMP-3 has been described as an important factor in the development of arthritis (Green et al 2003), asthma (Dahlen et al 1999), aneurism (Silence et al 2001), impaired wound healing (Fray et al 2003), Alzheimer’s disease (Yoshiyama et al 2000) and various cancers (Mercapide et al 2003; Wiesen and Werb 1996). Recent insights and studies demonstrate that association of MMP-3 with disease states (especially cancer) is uncertain, as many newer studies do not find a positive correlation between MMP-3 and disease.…”

pH stability of the stromelysin-1 catalytic domain and its mechanism of interaction with a glyoxal inhibitor

“…biphenyl]-4-hexanoic acid (UK-370106-COOH) (Scheme 1) a potent right hand side inhibitor of the metalloprotease stromelysin-1 with a carboxylate zinc-binding group [17,18]. We have converted the carboxyl zinc binding group of this inhibitor to a glyoxal group with 13 C-enrichment in the glyoxal aldehyde carbon (UK-370106-CO 13 CHO).…”

Drug delivery dressings

“…Other unusual combinations of dressings and therapeutic agents include a proprietary hydroxamate inhibitor of stromelysin-1 (MMP-3), known to be up-regulated in chronic wounds, as a solid dispersion within a lyophilised xanthan wafer (Fray et al, 2003;Matthews et al, 2008b); a cotton gauze saturated with adenosine triphosphate (ATP) vesicles (Chiang et al, 2007); and a poly(ethylene oxide -co-propylene oxide) hydrogel (Pluronic F127) containing the nitrogen oxide (NO) donor, S-nitrosoglutathione (Amadeu et al, 2008). These three examples of novel therapeutic agents contained in both traditional (cotton) and non-traditional (lyophilised wafer and hydrogel) carriers offer some examples of therapeutic agents, other than growth © Woodhead Publishing Limited, 2011 factors or antimicrobials, that may have a role to play in the future treatment of chronic wounds.…”