Carbamoylphosphonates, a new class of in vivo active matrix metalloproteinase inhibitors. 1. Alkyl- and cycloalkylcarbamoylphosphonic acids

Eli Breuer*, Claudio J. Salomon, Yiffat Katz, Weibin Chen, Shuiming Lu, Gerd Volker Röschenthaler, Rivka Hadar, Reuven Reich

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Matrix metalloproteinases (MMPs) are a family of over 20 zinc-dependent enzymes that hydrolyze connective tissue and are involved in a variety of diseases, which are associated with undesired tissue breakdown. This paper reports the synthesis, characterization, and biological evaluation of a novel class of MMP inhibitors based on the carbamoylphosphonic acid function. We report a series of 10 open chain N-alkylcarbamoylphosphonic acids (ranging from R = C1 to C6 groups), eight N-cycloalkylcarbamoylphosphonic acids (ranging from cyclopropyl to cyclooctyl rings), and four N,N-dialkylcarbamoylphosphonic acids. The compounds were evaluated in three in vitro models, which consisted of (a) the in vitro invasion across a reconstituted basement membrane, (b) determination of the IC50 values on recombinant MMP-1, MMP-2 MMP-3, MMP-8, and MMP-9 enzymes, and (c) an in vitro capillary formation model, which is a model of angiogenesis. Several of the compounds were also tested in an in vivo murine melanoma model. The following general conclusions have been reached: Most compounds show selectivity for MMP-2 over the other MMP subtypes examined. Cycloalkylcarbamoylphosphonic acids are more potent than comparable open-chain alkyl compounds. Optimal activity against MMP-2 among the cycloalkyl derivatives was shown by N-cyclopentylcarbamoylphosphonic acid (3m). N,N-Dialkylcarbamoylphosphonic acids that were examined showed weak or no activity. The compounds examined showed toxic effects neither in vitro nor in vivo in the concentrations used. Carbamoylphosphonic acids are water soluble at physiological pH and are stable indefinitely.

Original languageEnglish
Pages (from-to)2826-2832
Number of pages7
JournalJournal of Medicinal Chemistry
Volume47
Issue number11
DOIs
StatePublished - 20 May 2004

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