THE PHARMACOLOGICAL PROFILE OF CGP-28238, A NOVEL HIGHLY POTENT ANTIINFLAMMATORY COMPOUND

  • 1 January 1989
    • journal article
    • research article
    • Vol. 15  (11-12) , 501-509
Abstract
CGP 28238 (6-(2,4-difluorophenoxy)-5-methylsulfonylamino-1-indanone) exhibits very potent anti-inflammatory activity in rat adjuvant arthritis (ED40 = 0.05 mg/kg, p.o.) and pronounced analgesic and antipyretic activity in acute models in mice and rats (ED50 2-5 mg/kg, p.o.), but has clear advantages over reference NSAIDs with respect to gastro-intestinal tolerability. Threshold doses for gastro-intestinal ulcerogenicity in rats after single and repeated (10 .times.) doses were found to be 30 mg/kg, p.o., and prostaglandin (PGE2) production in rat gastric and ileal mucosa was only marginally inhibited (ED50 > 30 mg/kg, p.o.). On the other hand, PGE2 production in rat inflammatory exudate and thromboxane synthesis in rat blood were inhibited with ED50 values of 2 .ltoreq. 2 mg/kg, p.o. Although CGP 28238 does not inhibit cyclooxygenase in bovine seminal vesicle microsomal preparations (IC50 > 10-3 mol/l), potent inhibition of prostaglandin synthesis was shown in various in vitro systems using human and animal cells with IC50 values of < 10-6 mol/l. IL-1-stimulated bone resorption and PGE2 production in murine calvarial cultures were inhibited with IC50 values of 3 .times. 10-7 and 2 .times. 10-8 mol/l, respectively. 5-Lipoxygenase (murine macrophages), phospholipase A2 (human PMN) and phospholipase C (human platelets) were not inhibited. CGP 28238 may represent a novel highly potent anti-inflammatory compound with improved gastro-intestinal safety.