Journal
CHEMMEDCHEM
Volume 6, Issue 8, Pages 1471-1477Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201100153
Keywords
antitumor agents; drug design; enzymes; inhibitors; medicinal chemistry; phosphonates
Categories
Funding
- Grass Center for Drug Design and Synthesis of Novel Therapeutics
Ask authors/readers for more resources
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 similar to 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available