Prevention of progressive joint destruction in adjuvant induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR217840.

Abstract

Matrix metalloproteinase (MMP) has been implicated in joint destruction of chronic arthritis diseases, such as rheumatoid arthritis. FR217840 (2R)-1-([5-(4-fluorophenyl)-2-thienyl]sulfonyl)-N-hydroxy-4-(methylsulfonyl)-2-piperazinecarboxamide is a potent, orally active synthetic MMP inhibitor that inhibits human collagenases (MMP-1, MMP-8 and MMP-13), gelatinases (MMP-2 and MMP-9) and membrane type MMP (MT-MMP) (MT1-MMP/MMP-14). FR217840 also inhibits rat collagenase and gelatinase. We studied the effect of FR217840 on a rat adjuvant induced arthritis model. Although oral administration (days 1-21) of FR217840 (3.2, 10, 32 mg/kg) to adjuvant injected Lewis rats did not affect inflammation, as indicated by both hind paw swelling and histological inflammatory infiltration, FR217840 suppressed both bone destruction and serum pyridinoline content in a dose-dependent manner. Also, FR217840 (32 mg/kg) reduced tartrate-resistant acid phosphatase (TRAP) cell number in the ankle joints of rats with arthritis. These results indicate that FR217840 successfully suppressed joint destruction and suggest that FR217840 may have potential as a novel anti-rheumatic drug.

• Authors: Takeshi Ishikawa, Fusako Nishigaki, Susumu Miyata, Yoshitaka Hirayama, Kyoko Minoura, Junko Imanishi, Masahiro Neya, Tsuyoshi Mizutani, Yoshimasa Imamura, Yoshitaka Ohkubo, Seitaro Mutoh
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 508 Issue 1-3 Pg. 239-47 (Jan 31 2005) ISSN: 0014-2999 [Print] Netherlands
• PMID: 15680277 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Amino Acids
• FR217840
• Isoenzymes
• Matrix Metalloproteinase Inhibitors
• Piperazines
• Protease Inhibitors
• Tumor Necrosis Factor-alpha
• pyridinoline
• Acid Phosphatase
• Tartrate-Resistant Acid Phosphatase
• Collagenases
• MMP13 protein, human
• Matrix Metalloproteinase 13
• Matrix Metalloproteinases
• Mmp13 protein, rat
• Matrix Metalloproteinase 8
• Matrix Metalloproteinase 9
• Matrix Metalloproteinase 1

Topics

• Acid Phosphatase (metabolism)
• Amino Acids (blood)
• Animals
• Ankle Joint (diagnostic imaging, drug effects, pathology)
• Arthritis, Experimental (diagnostic imaging, pathology, prevention & control)
• Cell Line
• Cells, Cultured
• Collagenases (metabolism)
• Disease Progression
• Female
• Humans
• Isoenzymes (metabolism)
• Joint Diseases (diagnostic imaging, pathology, prevention & control)
• Matrix Metalloproteinase 1 (metabolism)
• Matrix Metalloproteinase 13
• Matrix Metalloproteinase 8 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases (metabolism)
• Piperazines (pharmacology, therapeutic use)
• Protease Inhibitors (pharmacology, therapeutic use)
• Radiography
• Rats
• Rats, Inbred Lew
• Tartrate-Resistant Acid Phosphatase
• Tumor Necrosis Factor-alpha (metabolism)