The normal healing of wounds is a complicated process. It proceeds through a number of well-defined and orchestrated stages. Fibronectin is a key component of the provisional matrix. Fibroblasts isolated from chronic dermal ulcers retain a normal ability to synthesize fibronectin. The fluids from chronic dermal ulcers contained fibronectin fragments. These fluids affect cells in a way compatible with matrix degradation. Fibronectin is a good substrate for Matrix metalloprotease-3 (MMP-3, stromelysin-1). Meanwhile, MMP activity (MMP-3 in particular) up-regulates in chronic dermal ulcers. Furthermore, MMP-3 degrades α1-antitrypsin, an endogenous inhibitor of neutrophil elastase. Thus, it is important to find a potent, selective inhibitor of MMP-3 for the topical treatment of chronic dermal ulcers. UK-370106 is a potent and highly selective MMP-3 (IC50=23 nM) and MMP-12 (IC50=42 nM) inhibitor.
UK-370106 shows >1200-fold higher potency than MMP-1, MMP-2, MMP-9, and MMP-14, and about 100-fold than MMP-13 and MMP-8. In addition, UK-370106 is found to be inactive versus zinc metalloproteases PCP and TACE and possesses the following inhibitory potencies versus MMP-2, MMP-7, MMP-8, MMP-9, and MMP-14. It also potently inhibits cleavage of [3H]-fibronectin by MMP-3 (IC50=320 nM), but does not inhibit cleavage of [3H]-gelatin by either MMP-2 or -9 up to the highest concentration tested. UK-370106 is not cytotoxic, nor affects the proliferation of fibroblasts, keratinocytes, or endothelial cells at 50-100 µM in vitro.
UK-370106 is cleared rapidly from plasma. But, it is slowly from dermal tissue in dermal wounds (rabbit). In a model of chronic dermal ulcers, UK-370106 for 6 days substantially inhibits MMP-3 ex vivo.
In summary, UK-370106 is a suitable candidate for progression to clinical trials in human chronic dermal wounds, such as venous ulcers.