title: 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.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan. ushiyama.shigeru.gf@daiichisankyo.co.jp
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ushiyama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamada
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Sei-ichiro
authors.initials: S
authors.lastname: Kumakura
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Inoue
authors.forename: Keisuke
authors.initials: K
authors.lastname: Suzuki
authors.forename: Akira
authors.initials: A
authors.lastname: Nakao
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kawara
authors.forename: Tomio
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001168:Arthritis / Q000188:drug therapy; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; C514354:apricoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2