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

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.