Diaryl-dithiolanes and -isothiazoles: COX-1/COX-2 and 5-LOX-inhibitory, *OH scavenging and anti-adhesive activities.
Three series of non-steroidal anti-inflammatory drugs (NSAIDs) inhibiting the cyclooxygenase/5-lipoxygenase (COX/5-LOX) pathways as such as formation of hydroxyl radicals and adhesion were prepared: 4,5-diaryl isothiazoles, 4,5-diaryl 3H-1,2-dithiole-3-thiones and 4,5-diaryl 3H-1,2-dithiole-3-ones. The aim of the present study was to develop substances which can intervene into the inflammatory processes via different mechanisms of action as multiple target non-steroidal anti-inflammatory drugs (MTNSAIDs) with increased anti-inflammatory potential. The current lead 11a was evaluated in COX-1/2, 5-LOX and (*)OH scavenging in vitro assays and in a static adhesion assay where it proved to inhibit adhesion. Moreover, 11a treatment attenuated expression of macrophage adhesion molecule-1 (Mac-1) on extravasated polymorphonuclear leukocytes (PMNs) which indicates that the activation was reduced. The assays used are predictive for the in vivo efficacy of test compounds as shown for 11a in a peritonitis model of acute inflammation in mice. Thus, the novel 5-LOX/COX and (*)OH inhibitor 11a possesses anti-inflammatory activity that, in addition to COX/5-LOX inhibition, implicates effects on leukocyte-endothelial interactions.
Scholz
Michael
M
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Johannes Gutenberg-University, Staudingerweg 5, DE-55128 Mainz, Germany.
Ulbrich
Holger K
HK
Soehnlein
Oliver
O
Lindbom
Lennart
L
Mattern
Andreas
A
Dannhardt
Gerd
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016166:Free Radical Scavengers; D017665:Hydroxyl Radical; D016859:Lipoxygenase Inhibitors; D016177:Macrophage-1 Antigen / Q000032:analysis / Q000187:drug effects; D051379:Mice; D009504:Neutrophils / Q000187:drug effects; D010538:Peritonitis / Q000188:drug therapy; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016166:Free Radical Scavengers; D016859:Lipoxygenase Inhibitors; D016177:Macrophage-1 Antigen; D013438:Sulfhydryl Compounds; D013844:Thiazoles; D017665:Hydroxyl Radical; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2