apricoxib and Inflammation

Apricoxib (CS-706), a small-molecule, orally active, selective COX-2 inhibitor, is under development by Tragara Pharmaceuticals Inc as an analgesic and anti-inflammatory agent, and also for its anticancer potential. The compound has desirable pharmacokinetic parameters, and has demonstrated good gastrointestinal tolerability and safety in preclinical studies and clinical trials. Phase IIa trial data indicated that apricoxib was a potent analgesic in the treatment of pain in postoperative dental surgery. At the time of publication, phase II trials assessing apricoxib in combination with anticancer drugs in patients with breast, lung and pancreatic cancer were ongoing. Evidence for the anticancer activity of oral apricoxib appears to be highly promising. However, the market success of apricoxib will depend mainly on long-term safety trials, which are needed to establish the cardiovascular safety of the drug when administered alone or in combination with other agents in cancer chemotherapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Cyclooxygenase 2 Inhibitors; Humans; Inflammation; Neoplasms; Pain; Pyrroles; Sulfonamides

We report here the preclinical anti-inflammatory profile of CS-706 [2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole], a novel cyclooxygenase-2 (COX-2) selective inhibitor. CS-706 selectively inhibited COX-2 in a human whole blood assay with an IC(50) of 0.31 microM, compared with an IC(50) of 2.2 microM for COX-1. The selectivity ratio of CS-706 was higher than those of the conventional non-steroidal anti-inflammatory drugs naproxen, indomethacin, and Diclofenac-Na, whereas it was lower than those of rofecoxib, valdecoxib and etoricoxib. It was similar to that of celecoxib. The pharmacokinetic profile of CS-706 showed rapid absorption and dose-proportional exposure after oral administration to rats. CS-706 inhibited prostaglandin E(2) production in inflamed tissue induced by yeast-injection in rats with potency similar to that of indomethacin. However, it inhibited gastric mucosal prostaglandin E(2) production in normal rats weakly compared with indomethacin. CS-706 ameliorated both yeast-induced inflammatory acute pain (ED(50)=0.0090 mg/kg) and adjuvant-induced chronic arthritic pain (ED(50)=0.30 mg/kg) in rats. CS-706 showed more potent antinociceptive activity than celecoxib and rofecoxib in these models. In an adjuvant-induced arthritic model in rats, CS-706 suppressed foot swelling prophylactically with an ID(50) of 0.10 mg/kg/day, and decreased foot swelling in the established arthritis therapeutically in a dose range of 0.040 to 1.0 mg/kg/day. Single administration of up to 100 mg/kg of CS-706 induced no significant gastric lesions in rats. In conclusion, CS-706 is a COX-2-selective inhibitor with a potent antinociceptive and anti-inflammatory activity and a gastric safety profile.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Arthritis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Inflammation; Inhibitory Concentration 50; Pain; Pain Measurement; Pyrroles; Rats; Rats, Inbred Lew; Rats, Wistar; Sulfonamides