Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects.

Abstract

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.

• Authors: Shigeru Ushiyama, Tomoko Yamada, Yukiko Murakami, Sei-ichiro Kumakura, Shin-ichi Inoue, Keisuke Suzuki, Akira Nakao, Akihiro Kawara, Tomio Kimura
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 578 Issue 1 Pg. 76-86 (Jan 06 2008) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17920584 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Cyclooxygenase 2 Inhibitors
• Pyrroles
• Sulfonamides
• apricoxib
• Cyclooxygenase 1
• Cyclooxygenase 2

Topics

• Administration, Oral
• Animals
• Anti-Inflammatory Agents (administration & dosage, adverse effects, pharmacokinetics)
• Arthritis (drug therapy)
• Cyclooxygenase 1 (drug effects, metabolism)
• Cyclooxygenase 2 (drug effects, metabolism)
• Cyclooxygenase 2 Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Humans
• Inflammation (drug therapy)
• Inhibitory Concentration 50
• Pain (drug therapy)
• Pain Measurement
• Pyrroles (administration & dosage, adverse effects, pharmacokinetics)
• Rats
• Rats, Inbred Lew
• Rats, Wistar
• Sulfonamides (administration & dosage, adverse effects, pharmacokinetics)