title: Orally active, antimetastatic, nontoxic diphenyl ether-derived carbamoylphosphonate matrix metalloproteinase inhibitors.
abstract: Seven 4-phenoxybenzenesulfonamidopolymethylene carbamoylphosphonates (CPOs) bearing two to eight methylene units in the polymethylene chain were synthesized and evaluated as matrix metalloproteinase (MMP) inhibitors. The five lowest homologues [(CH₂)₂-₆] are selective MMP-2 inhibitors, whereas the two with the longest linkers [(CH₂)₇,₈] lack inhibitory activity. The most potent homologues are those with (CH₂)₅,₆; these two were evaluated for antimetastatic activity in a murine melanoma model and showed good potency both by oral and intraperitoneal administration without any toxic--including musculoskeletal--side effects. In contrast to the previously reported cis-ACCP, which was shown to inhibit MMP-2 for ∼30 min, the new compounds inhibit MMP activity for the duration of measurement, lasting several hours. Pharmacokinetic evaluation revealed, on the one hand, low oral bioavailability; on the other hand, a relatively large calculated volume of distribution, consistent with the observed reversible absorption of CPO 5 to hydroxyapatite, as a model for bone.
authors.affiliation: Institute for Drug Research, The Hebrew University of Jerusalem, School of Pharmacy, P.O. Box 12065, Jerusalem 91120, Israel.
authors.forename: Julia
authors.initials: J
authors.lastname: Frant
authors.forename: Ainelly
authors.initials: A
authors.lastname: Veerendhar
authors.forename: Tamir
authors.initials: T
authors.lastname: Chernilovsky
authors.forename: Shlomo
authors.initials: S
authors.lastname: Nedvetzki
authors.forename: Olga
authors.initials: O
authors.lastname: Vaksman
authors.forename: Amnon
authors.initials: A
authors.lastname: Hoffman
authors.forename: Eli
authors.initials: E
authors.lastname: Breuer
authors.forename: Reuven
authors.initials: R
authors.lastname: Reich
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003038:Cobamides; D003510:Cyclohexanes; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D063065:Organophosphonates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010647:Phenyl Ethers / Q000737:chemistry*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D003038:Cobamides; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D063065:Organophosphonates; D010647:Phenyl Ethers; D020033:Protein Isoforms; C465815:adenosylcobinamide 2-chlorophenyl phosphate; C031538:phenyl ether; D020782:Matrix Metalloproteinases