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.

  title={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.},
  author={Amnon Hoffman and Bashir Qadri and Julia Frant and Yiffat Katz and Sudhakar R. Bhusare and Eli Breuer and Rivka Hadar and Reuven Reich},
  journal={Journal of medicinal chemistry},
  volume={51 5},
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 approximately 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… 

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

Seven 4‐phenoxybenzenesulfonamidopolymethylene carbamoylphosphonates bearing two to eight methylene units in the polymethylene chain were synthesized and evaluated as matrix metalloproteinase (MMP) inhibitors, revealing low oral bioavailability and a relatively large calculated volume of distribution, consistent with the observed reversible absorption of CPO 5 to hydroxyapatite, as a model for bone.

Carbamoylphosphonates control tumor cell proliferation and dissemination by simultaneously inhibiting carbonic anhydrase IX and matrix metalloproteinase-2. Toward nontoxic chemotherapy targeting tumor microenvironment.

It is discovered that CPOs also inhibit carbonic anhydrases (CAs), especially the IX and XII isoforms identified as cancer promoting factors, and can be regarded as novel nontoxic drug candidates for tumor microenvironment targeted chemotherapy acting by two synergistic mechanisms.

N-O-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in Vivo Antiangiogenic Activity.

The optimization effort to identify novel N-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward M MP-2, MMP-9, and MMP -14 with respect to the previously discovered compound 1 is reported.

Synthesis of Enantiomeric Aminoalkylcarbamoylphosphonates and Their Evaluation as Dual-Action Anticancer MMP and Carbonic Anhydrase Inhibitors

The stereoselective synthesis and the evaluation of the biological properties of a pair of enantiomeric aminoalkylcarbamoylphosphonates, which have been enantioselectively synthesized from l-serine, using functional group-transformations are described.

The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma

It is clearly time to move on from the dogma of viewing MMP inhibition as intractable, and multiple studies indicate that modulating MMP activity can improve immunotherapy.

Computational and Experimental Progress on the Structure and Chemical Reactivity of Procyanidins: Their Potential as Metalloproteinases Inhibitors

The advances of experimental and computational investigations carried out to date on the structure and chemical reactivity of procyanidins (PCs) are presented, to support the basis of their potential use as MMP inhibitors.

Glyco-Phospho-Glycero Ether Lipids (GPGEL): synthesis and evaluation as small conductance Ca2+-activated K+ channel (SK3) inhibitors

It is shown that the presence of one anionic charge in the polar head group does not alter the SK3 channel inhibition and provides insights into the future development of a class of migration-targeted anticancer agents.



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

Most compounds show selectivity for MMP-2 over the other MMP subtypes examined, and Cycloalkylcarbamoylphosphonic acids are more potent than comparable open-chain alkyl compounds.

Carbamoylphosphonate Matrix Metalloproteinase Inhibitors 3: In vivo Evaluation of Cyclopentylcarbamoylphosphonic Acid in Experimental Metastasis and Angiogenesis

A nontoxic MMP-2–selective inhibitor effective at nanomolar range on recombinant MMP is discovered and significantly inhibited cellular invasion and capillary formation in vitro and indicates that the compound might also be effective in treatment of primary tumor growth in reduction, or at least in prevention, of further tumor growth, thereby reducing the tumor burden of the patient by a nontoxic approach.

Carbamoylphosphonate-based matrix metalloproteinase inhibitor metal complexes: solution studies and stability constants. Towards a zinc-selective binding group

In vivo potent inhibitors based on the carbamoylphosphonic group as a putative zinc binding group are developed and are expected to be useful for the design of new selective inhibitors.

A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas

Although COL-3 was generally well-tolerated, there were no objective responses and 5(33%) patients experienced disease progression during the first 8 weeks of treatment, which exceeded the criteria established a priori with regard to pursuing further evaluations ofCOL-3 in STS.

Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug

SAHA has many protein targets whose structure and function are altered by acetylation, including chromatin-associated histones, nonhistone gene transcription factors and proteins involved in regulation of cell proliferation, migration and death.

The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors.

The design of small molecular weight MMP inhibitors, a brief description of available three-dimensional MMP structures, a review of the proposed therapeutic utility of M MP inhibitors, and a clinical update of compounds that have entered clinical trials in humans are described.

Recent non-hydroxamate matrix metalloproteinase inhibitors

This review attempts to rationalise the failure of hydroxamates as MMPI, critically reviews publications and patents of the last few years, which report new non-hydroxamate based MMPIs, and summarises factors that are considered important for success in developing clinically useful M MPIs.

Therapeutic developments in matrix metalloproteinase inhibition

The current status of the understanding of MMPs and how they participate in normal and functional ECM degradation is summarized and areas where future efforts to develop therapeutic strategies might be most beneficial and productive are proposed.