Prevention of progressive joint destruction in adjuvant induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR217840.
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.
Ishikawa
Takeshi
T
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan. takeshi_ishikawa@po.fujisawa.co.jp
Nishigaki
Fusako
F
Miyata
Susumu
S
Hirayama
Yoshitaka
Y
Minoura
Kyoko
K
Imanishi
Junko
J
Neya
Masahiro
M
Mizutani
Tsuyoshi
T
Imamura
Yoshimasa
Y
Ohkubo
Yoshitaka
Y
Mutoh
Seitaro
S
D000135:Acid Phosphatase / Q000378:metabolism; D000596:Amino Acids / Q000097:blood; D000818:Animals; D000843:Ankle Joint / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D002460:Cell Line; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007592:Joint Diseases / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011859:Radiography; D051381:Rats; D011917:Rats, Inbred Lew; D000071681:Tartrate-Resistant Acid Phosphatase; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000596:Amino Acids; C501981:FR217840; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; C015484:pyridinoline; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C507083:Mmp13 protein, rat; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1