Carbamoylphosphonates, a new class of in vivo active matrix metalloproteinase inhibitors. 1. Alkyl- and cycloalkylcarbamoylphosphonic acids.
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 = C(1) to C(6) 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 IC(50) 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.
Breuer
Eli
E
Department of Medicinal Chemistry, The School of Pharmacy, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem, 91120 Israel. breuer@cc.huji.ac.il
Salomon
Claudio J
CJ
Katz
Yiffat
Y
Chen
Weibin
W
Lu
Shuiming
S
Röschenthaler
Gerd-Volker
GV
Hadar
Rivka
R
Reich
Reuven
R
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001485:Basement Membrane / Q000187:drug effects / Q000473:pathology; D002196:Capillaries / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009361:Neoplasm Invasiveness; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D012995:Solubility; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; C487367:N-cyclopentylcarbamoylphosphonic acid; D063065:Organophosphonates; D015032:Zinc