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Orally Active, Antimetastatic, Nontoxic Diphenyl Ether‐Derived Carbamoylphosphonate Matrix Metalloproteinase Inhibitors
Author(s) -
Frant Julia,
Veerendhar Ainelly,
Chernilovsky Tamir,
Nedvetzki Shlomo,
Vaksman Olga,
Hoffman Am,
Breuer Eli,
Reich Reuven
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100153
Subject(s) - chemistry , bioavailability , matrix metalloproteinase , potency , ether , pharmacokinetics , pharmacology , matrix metalloproteinase inhibitor , absorption (acoustics) , metalloproteinase , stereochemistry , oral administration , biochemistry , in vitro , medicine , organic chemistry , physics , acoustics
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 ∼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.