Benzo[d]isothiazol-3-yl-benzamidines: a class of protective agents on culture of human cartilage and chondrocytes stimulated by IL-1beta.
New derivatives of N-benzo[d]isothiazol-3-yl-benzamidine 6 a were synthesized as nonacidic anti-inflammatory/antidegenerative agents. We investigated the influence of the amidines 6 a-j on the production of NO, PGE(2), MMP-3, COX-2, ROS, and GAGs, key molecules involved in cartilage destruction in osteoarthritic diseases. The antidegenerative properties of the novel designed derivatives 6 b-j were improved with respect to N-benzo[d]isothiazol-3-yl-benzamidine 6 a. All of the compounds 6 a-j promoted the reduction of most of the IL-1beta-induced harmful effects. Derivatives 6 d, 6 h, and 6 j were the most potent of all the tested compounds, particularly in the human chondrocyte culture model.
Vicini
Paola
P
Pharmaceutical Department, Faculty of Pharmacy, University of Parma, V.le G.P. Usberti 27/A, 43100 Parma, Italy. pvicini@ipruniv.cce.unipr.it
Incerti
Matteo
M
Cardile
Venera
V
Garufi
Floriana
F
Ronsisvalle
Simone
S
Panico
Anna Maria
AM
D000578:Amidines / Q000737:chemistry*; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D001550:Benzamidines / Q000138:chemical synthesis / Q000494:pharmacology*; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy*; D020011:Protective Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
D000578:Amidines; D000893:Anti-Inflammatory Agents; D001550:Benzamidines; D006025:Glycosaminoglycans; D053583:Interleukin-1beta; D020011:Protective Agents; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D019278:Matrix Metalloproteinase 3