Carbamoylphosphonate matrix metalloproteinase inhibitors 6: cis-2-aminocyclohexylcarbamoylphosphonic acid, a novel orally active antimetastatic matrix metalloproteinase-2 selective inhibitor-synthesis and pharmacodynamic and pharmacokinetic analysis

Amnon Hoffman*, Bashir Qadri, Julia Frant, Yiffat Katz, Sudhakar R. Bhusare, Eli Breuer, Rivka Hadar, Reuven Reich

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

cis-2-Aminocyclohexylcarbamoylphosphonic acid (cis-ACCP) was evaluated in vitro and in two in vivo cancer metastasis models. It reduced metastasis formation in mice by ∼90% when administered by a repetitive once daily dosing regimen of 50 mg/kg via oral or intraperitoneal routes and was nontoxic up to 500 mg/kg, following intraperitoneal administration daily for two weeks. Pharmacokinetic investigation of cis-ACCP in rats revealed distribution restricted into the extracellular fluid, which is the site of action for the antimetastatic activity and rapid elimination (t1/2 ∼ 19 min) from blood. Sustained and prolonged absorption (t1/2 ∼126 min) occurred via paracellular mechanism along the small and large intestine with overall bioavailability of 0.3%. The in vivo concentrations of cis-ACCP in the blood in rats was above the minimal concentration for antimetastatic/MMP- inhibitory activity, thus explaining the prolonged action following once daily administration. Finally, 84% of the intravenously administered cis-ACCP to rats was excreted intact in the urine.

Original languageAmerican English
Pages (from-to)1406-1414
Number of pages9
JournalJournal of Medicinal Chemistry
Volume51
Issue number5
DOIs
StatePublished - 13 Mar 2008

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