Synthesis, Structure−Activity Relationships, and in Vivo Evaluations of Substituted Di-tert-butylphenols as a Novel Class of Potent, Selective, and Orally Active Cyclooxygenase-2 Inhibitors. 2. 1,3,4- and 1,2,4-Thiadiazole Series<SUP>1</SUP><BBR RID="jm980570yb00001">

Two isoforms of the cyclooxygenase (COX) enzyme have been identified:  COX-1, which is expressed constitutively, and COX-2, which is induced in inflammation. Recently, it has been shown that selective COX-2 inhibitors have antiinflammatory activity and lack the GI side effects typically associated with NSAIDs. Initial mass screening and subsequent SAR studies have identified <BO>6b</BO> (PD164387) as a potent, selective, and orally active COX-2 inhibitor. It had IC<INF>50</INF> values of 0.14 and 100 μM against recombinant human COX-2 and purified ovine COX-1, respectively. It inhibited COX-2 activity in the J774A.1 cell line with an IC<INF>50</INF> of 0.18 μM and inhibited COX-1 activity in platelets with an IC<INF>50</INF> of 3.1 μM. The choline salt of compound <BO>6b</BO> was also orally active in vivo with an ED<INF>40</INF> 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 that this compound inhibited gastric prostaglandin E<INF>2</INF> (PGE<INF>2</INF>) production in gastric mucosa by 77% but caused minimal GI damage. SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes.