Orally Active, Antimetastatic, Nontoxic Diphenyl Ether-Derived Carbamoylphosphonate Matrix Metalloproteinase Inhibitors

Julia Frant, Ainelly Veerendhar, Tamir Chernilovsky, Shlomo Nedvetzki, Olga Vaksman, Amnon Hoffman, Eli Breuer*, Reuven Reich

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 [(CH 2) 2-6] are selective MMP-2 inhibitors, whereas the two with the longest linkers [(CH 2) 7,8] lack inhibitory activity. The most potent homologues are those with (CH 2) 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 ~30min, 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.

Original languageAmerican English
Pages (from-to)1471-1477
Number of pages7
JournalChemMedChem
Volume6
Issue number8
DOIs
StatePublished - 1 Aug 2011

Keywords

  • Antitumor agents
  • Drug design
  • Enzymes
  • Inhibitors
  • Medicinal chemistry
  • Phosphonates

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