Abstract
The pathology of rheumatoid arthritis includes synoviocyte proliferation and inflammatory mediator expression, which may result from dysregulated epigenetic control by histone deacetylase (HDAC). Thus, HDAC inhibitors may be useful for treating inflammatory disease. This was a preclinical study of the HDAC inhibitor, MPT0G009. The IC50 values of MPT0G009 for HDAC1, 2, 3, 6 and 8 enzymatic activities were significantly lower than those for the currently marketed HDAC inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat). In addition, MPT0G009 markedly inhibited cytokine secretion and macrophage colony-stimulating factor/receptor activator of nuclear factor kappa B ligand-induced osteoclastogenesis by macrophages (50 ng/ml each). These MPT0G009 effects on cytokine secretion and osteoclast formation were reduced by the overexpression of HDAC 1 (class I HDAC) and 6 (class II HDAC) in cells, suggesting that these effects were due to the inhibition of its activity. In an in vivo rat model, oral administration of MPT0G009 (25 mg/kg) significantly inhibited paw swelling and bone destruction. Furthermore, compared with SAHA, MPT0G009 exhibited longer half-life (9.53 h for oral administration) and higher oral bioavailability (13%) in rats. These results established the preclinical anti-arthritic efficacy and pharmacokinetic parameters of MPT0G009, which may provide a new therapeutic approach for treating inflammatory arthritis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Administration, Oral
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Animals
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents / therapeutic use
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Arthritis, Experimental / drug therapy
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Arthritis, Experimental / pathology
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Arthritis, Rheumatoid / drug therapy*
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Arthritis, Rheumatoid / enzymology*
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Arthritis, Rheumatoid / pathology
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects
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Cytokines / biosynthesis
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Disease Models, Animal
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacokinetics*
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylase Inhibitors / therapeutic use*
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Histones / metabolism
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Hydroxamic Acids / administration & dosage
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacokinetics*
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Hydroxamic Acids / pharmacology
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Hydroxamic Acids / therapeutic use*
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Inflammation Mediators / metabolism
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Inhibitory Concentration 50
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Macrophage Colony-Stimulating Factor / pharmacology
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Maximum Tolerated Dose
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Mice
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Osteoclasts / drug effects
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Osteoclasts / metabolism
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Osteoclasts / pathology
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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RANK Ligand / pharmacology
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Rabbits
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Rats
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Recombinant Proteins / metabolism
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Sulfonamides / chemistry
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Sulfonamides / pharmacokinetics*
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use*
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Synovial Membrane / pathology
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Vorinostat
Substances
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Anti-Inflammatory Agents
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Cytokines
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Histone Deacetylase Inhibitors
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Histones
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Hydroxamic Acids
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Inflammation Mediators
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Protein Isoforms
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RANK Ligand
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Recombinant Proteins
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Sulfonamides
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3-(1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl)-N-hydroxyacrylamide
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Vorinostat
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Macrophage Colony-Stimulating Factor