Carbamoylphosphonate Matrix Metalloproteinase Inhibitors 6: <i>cis</i>-2-Aminocyclohexylcarbamoylphosphonic Acid, A Novel Orally Active Antimetastatic Matrix Metalloproteinase-2 Selective Inhibitor—Synthesis and Pharmacodynamic and Pharmacokinetic Analysis

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

doi:10.1021/jm800674s

Cited by 4 publications

(15 citation statements)

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“…Melting points were determined on a Kofler hotstage apparatus and are uncorrected. 1 H and 13 C NMR spectra were determined with a Varian Gemini 200 MHz spectrometer or a Bruker Avance III HD 400 MHz spectrometer. Chemical shifts (δ) are reported in parts per million downfield from tetramethylsilane and referenced from solvent references.…”

Section: Methodsmentioning

confidence: 99%

“…Coupling constants J are reported in hertz. 13 C NMR spectra were fully decoupled. The following abbreviations are used: singlet (s), doublet (d), triplet (t), double− doublet (dd), broad (br), and multiplet (m).…”

Section: Methodsmentioning

confidence: 99%

“…Brownish oil, 95% yield. 1 (R)-4-tert-Butoxy-3-(N-isopropoxyphenylsulfonamido)-4-oxobutan-1-aminium Acetate (13). The title compound was prepared from Cbz-derivative 10 following the general procedure.…”

Section: Methodsmentioning

confidence: 99%

“…9 Nowadays, it is widely accepted that selective inhibitors of only those MMPs validated as targets in anticancer therapy (i.e., MMP-2, MMP-9, and MMP-14) should be used in order to have efficacy and to avoid side effects due to cross-inhibition of antitarget proteases. Successful examples of this strategy are represented by SB-3CT, 10 a selective MMP-2 and MMP-9 inhibitor able to reduce prostate cancer metastasis to the bone 11 and T-cell lymphoma metastasis to the liver 12 in animal models, and cis-ACCP, 13 a MMP-2 selective inhibitor with antimetastatic activity. A peculiar case is represented by NSC405020, an allosteric selective inhibitor of MMP-14 able to bind the hemopexin domain which significantly inhibited tumor growth in an animal model of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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Matrix metalloproteinases (MMPs) have been shown to be involved in tumor-induced angiogenesis. In particular, MMP-2, MMP-9, and MMP-14 have been reported to be crucial for tumor angiogenesis and the formation of metastasis, thus becoming attractive targets in cancer therapy. Here, we report our optimization effort to identify novel N-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward MMP-2, MMP-9, and MMP-14 with respect to the previously discovered compound 1. A new series of hydroxamates was designed, synthesized, and tested for their antiangiogenic activity using in vitro assays with human umbilical vein endothelial cells (HUVECs). A nanomolar MMP-2, MMP-9, and MMP-14 inhibitor was identified, compound 3, able to potently inhibit angiogenesis in vitro and also in vivo in the matrigel sponge assay in mice. Finally, X-ray crystallographic and docking studies were conducted for compound 3 in order to investigate its binding mode to MMP-9 and MMP-14.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…The compound reduced metastasis in melanoma and prostate in vivo cancer models. 111 Another option that has been explored for more selective MMP inhibition is targeting the hemopexin domain of MMPs, which is less conserved than the catalytic site. The quest to improve these small-molecule inhibitors continues owing to their pharmacological stability and ease of administration.…”

Section: Novel Mmpis and Inhibition Strategies Small Moleculesmentioning

confidence: 99%

Matrix metalloproteinase protein inhibitors: highlighting a new beginning for metalloproteinases in medicine

Sagi¹,

Talmi-Frank²,

Arkadash³

et al. 2016

MNM

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The development of therapeutic matrix metalloproteinase (MMP) inhibitors has evolved from broad-spectrum peptidomimetic inhibitors with deleterious side effects, to highly selective agents. These range from small molecules to antibodies, antisense inhibitors, and engineered N-terminal tissue inhibitors of metalloproteinase domain. The advances in inhibitor design along with promising new global molecular insights into MMP structures, the protease web, and the role of extracellular matrix in diseases have contributed toward a renewed interest in using MMPs as valid drug targets. This review aims to address the advances and challenges concerning the design, development, and current status of anti-MMP agents in this new era of post-broad-spectrum MMP inhibitors. Highly selective inhibitors of MMPs promise to usher in an era of specific targeting of diseased tissue proteolysis networks, with markedly reduced negative repercussions, and to uncover the molecular and mechanistic roles of MMP isoforms in cancer, inflammation, and infection.

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Selective Inhibitors of Medium-Size S1′ Pocket Matrix Metalloproteinases: A Stepping Stone of Future Drug Discovery

et al. 2022

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Among various matrix metalloproteinases (MMPs), MMPs having medium-size S1′ pockets are established as promising biomolecular targets for executing crucial roles in cancer, cardiovascular diseases, and neurodegenerative diseases. However, no such MMP inhibitors (MMPIs) are available to date as drug candidates despite a lot of continuous research work for more than three decades. Due to a high degree of structural resemblance among these MMPs, designing selective MMPIs is quite challenging. However, the variability and uniqueness of the S1′ pockets of these MMPs make them promising targets for designing selective MMPIs. In this perspective, the overall structural aspects of medium-size S1′ pocket MMPs including the unique binding patterns of enzyme−inhibitor interactions have been discussed in detail to acquire knowledge regarding selective inhibitor designing. This overall knowledge will surely be a curtain raiser for the designing of selective MMPIs as drug candidates in the future.

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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

Abstract: 018. Figure 4 depicts a recently obtained cocrystal structure (PDB code 2ONC).

Cited by 4 publications

References 0 publications

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

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

Matrix metalloproteinase protein inhibitors: highlighting a new beginning for metalloproteinases in medicine

Selective Inhibitors of Medium-Size S1′ Pocket Matrix Metalloproteinases: A Stepping Stone of Future Drug Discovery

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