title: 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.
authors.affiliation: Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, U.K. jonathan_fray@sandwich.pfizer.com
authors.forename: M Jonathan
authors.initials: MJ
authors.lastname: Fray
authors.forename: Roger P
authors.initials: RP
authors.lastname: Dickinson
authors.forename: John P
authors.initials: JP
authors.lastname: Huggins
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Occleston
mesh_terms: 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
chemical_list: 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