Prevention of progressive joint destruction in collagen-induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR255031.

Abstract

FR255031 (2-[(7S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxido-4-(2-pyridinylcarbonyl)hexahydro-1,4-thiazepin-7-yl]-N-hydroxyacetamide) is a novel synthetic matrix metalloproteinase (MMP) inhibitor that inhibits human collagenases (MMP-1, MMP-8 and MMP-13), gelatinases (MMP-2 and MMP-9) and membrane type 1 MMP (MT1-MMP/MMP-14). FR255031 also inhibits rat collagenase and gelatinase. We studied the effect of FR255031 and Trocade, an inhibitor of collagenase and MMP-14, on a rat collagen-induced arthritis (CIA) model. Rat CIA was induced by intradermal injection of type II collagen (IIC) and oral administration of FR255031 or Trocade was performed for 28 days. Body weight loss, hind paw swelling, elevation of serum anti-IIC antibody, and histological and radiographic scores were evaluated. FR255031 markedly inhibited cartilage degradation in a dose-dependent manner in the CIA model, but Trocade failed to prevent the degradation. FR255031 at a dose of 100 mg kg(-1) also had statistically significant effects on bone destruction and pannus formation and on the recovery of body weight loss on day 28. These results indicate that FR255031 is effective for rat CIA, especially on joint cartilage destruction. These data suggest that as well as collagenases or MT-MMP, gelatinases are also involved in joint destruction in arthritis.

• Authors: Takeshi Ishikawa, Fusako Nishigaki, Susumu Miyata, Yoshitaka Hirayama, Kyoko Minoura, Junko Imanishi, Masahiro Neya, Tsuyoshi Mizutani, Yoshimasa Imamura, Yoichi Naritomi, Hidetsugu Murai, Yoshitaka Ohkubo, Akira Kagayama, Seitaro Mutoh
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 144 Issue 1 Pg. 133-43 (Jan 2005) ISSN: 0007-1188 [Print] England
• PMID: 15644877 (Publication Type: Evaluation Study, Journal Article)

Chemical References

• FR255031
• Matrix Metalloproteinase Inhibitors
• Thiazepines
• Matrix Metalloproteinases

Topics

• Animals
• Arthritis, Experimental (enzymology, pathology, prevention & control)
• Body Weight (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Edema (pathology, prevention & control)
• Female
• Hindlimb (diagnostic imaging, pathology)
• Humans
• Inflammation (pathology, prevention & control)
• Joint Diseases (prevention & control)
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases (chemical synthesis, chemistry, pharmacokinetics)
• Molecular Structure
• Radiography
• Rats
• Rats, Inbred Lew
• Thiazepines (pharmacology)