Synthesis, structure - Activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, andorally active cyclooxygenase-2 inhibitors. 2. 1,3,4- and 1,2,4-thiadiazoleseries

Two isoforms of the cyclooxygenase (COX) enzyme have been identified: COX-1 , which is expressed constitutively, and COX-2, which is induced in inflamm ation. Recently, it has been shown that selective COX-2 inhibitors have ant iinflammatory activity and lack the GI side effects typically associated wi th NSAIDs. Initial mass screening and subsequent SAR studies have identifie d 6b (PD164387) as a potent, selective, and orally active COX-2 inhibitor. It had IC50 values of 0.14 and 100 mu M against recombinant human COX-2 and purified ovine COX-1, respectively. It inhibited COX-2 activity in the J77 4A.1 cell line with an IC50 Of 0.18 mu M and inhibited COX-1 activity in pl atelets with an IC50 of 3.1 mu M. The choline salt of compound 6b was also orally active in vivo with an ED40 Of 7.1 mg/kg in the carrageenan footpad edema (CFE) assay. In vivo studies in rats at a dose of 100 mg/kg showed th at this compound inhibited gastric prostaglandin E-2 (PGE(2)) production in gastric mucosa by 77% but caused minimal GI damage. SAR studies of this ch emical series revealed that the potency and selectivity are very sensitive to minor structural changes.