A potent, selective inhibitor of matrix metalloproteinase-3 for the topical treatment of chronic dermal ulcers.
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.
Fray
M Jonathan
MJ
Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, U.K. jonathan_fray@sandwich.pfizer.com
Dickinson
Roger P
RP
Huggins
John P
JP
Occleston
Nicholas L
NL
D000279:Administration, Cutaneous; D000818:Animals; D002208:Caproates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D005353:Fibronectins / Q000737:chemistry; D005780:Gelatin / Q000737:chemistry; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D011083:Polycyclic Compounds; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012871:Skin Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014456:Ulcer / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014633:Valine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C476600:3-(((2,2-dimethyl-1-(((2-methoxy-1-phenylethyl)amino)carbonyl)propyl)amino)carbonyl)-6-(3-methyl-4-phenylphenyl)hexanoic acid; D002208:Caproates; D005353:Fibronectins; D061965:Matrix Metalloproteinase Inhibitors; D011083:Polycyclic Compounds; D011480:Protease Inhibitors; D005780:Gelatin; D019278:Matrix Metalloproteinase 3; D014633:Valine