1,3-diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives: A new series of potent and selective COX-2 inhibitors in which a sulfonyl group is not a structural requisite

Novel tetrahydro-2H-isoindoles have been prepared and evaluated as inhibito rs of the COX-2 isoenzyme. A 1,S-diaryl substitution on the central polycyc lic ring system and absence of a sulfonyl moiety are the two structural fea tures of this chemical series. A short and easy synthetic pathway produced several derivatives which were shown to be potent and selective COX-2 vs CO X-1 inhibitors (IC50 = 0.6-100 nM for COX-2, 100->1000 nM for COX-1). Struc tural modifications established that a bicyclic ring appended to the pyrrol e nucleus and 4,4'-difluoro substitution on the phenyl rings were optimal f or high inhibitory potency. Activity was confirmed in the human whole blood assay and subsequently in the murine air-pouch model in which in vivo PGE2 inhibitory activity was evaluated with respect to gastric tolerance (ED50 for inhibition of exudate PGE2 of 3 mg/kg and gastric PGEB of 20 mg/kg). Ga stric tolerance was further assessed after administration to mice of high d oses (up to 400 mg/kg) of the inhibitors by measurement of gastric damage. This panel of studies allowed selection of a number of tetrahydro-2H-isoind oles which were compared in the adjuvant-induced arthritis model. Compounds 32 and 37 showed the most potent activity with ED50 values for edema inhib ition in the noninjected paw of 0.35 and 0.15 mg/kg/day, respectively, afte r oral administration. In addition, this interesting antiinflammatory profi le was accompanied by a protective effect against arthritis-induced osteope nia, the decrease being 50% with a dose of 0.25 mg/kg/day.