Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors

Abstract A new class of selective cyclooxygenase-2 (COX-2) inhibitors has been identified by high throughput screening. Structurally distinct from previously described selective COX-2 inhibitors, these benzopyrans contain a carboxylic acid function and CF 3 functionality. The compound SC-75416 is a representative of this class. A range if in vitro and in vivo tests were employed to characterize its potency and selectivity. Using human recombinant enzymes, this compound displays a concentration that provides 50% inhibition (IC 50 ) of 0.25 μM for COX-2 and 49.6 μM for COX-1. A mutation of the side pocket residues in COX-2 to COX-1 had little effect on potency suggesting that these inhibitors bind in a unique manner in COX-2 distinct from COX-2 inhibiting diaryl heterocycles. Using rheumatoid arthritic synovial cells stimulated with interleukin-1β (IL-1β) and washed platelets the compound displayed IC 50 of 3 nM and 400 nM respectively. Potency and selectivity was maintained but predictably right shifted in whole blood with IC 50 of 1.4 μM for lipopolysaccharide (LPS) stimulated induction of COX-2 and > 200 μM for inhibition of platelet thromboxane production. SC-75416 is 89% bioavailable and its in vivo half life is sufficient for once a day dosing. In the rat air pouch model of inflammation, the compound inhibited PGE 2 production with an effective dose that provides 50% inhibition (ED 50 ) of 0.4 mg/kg, while sparing gastric prostaglandin E2 (PGE 2 ) production with an ED 50 of 26.5 mg/kg. In a model of acute inflammation and pain caused by carrageenan injection into the rat paw, the compound reduced edema and hyperalgesia with ED 50 s of 2.7 and 4 mg/kg respectively. In a chronic model of arthritis the compound demonstrated an ED 50 of 0.081 mg/kg and an ED 80 of 0.38 mg/kg. In a model of neuropathic pain, SC-75416 had good efficacy. This compound's unique chemical structure and effect on COX enzyme binding and activity as well as its potency and selectivity may prove useful in treating pain and inflammation.