Analgesic agents without gastric damage: design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors.
In order to create novel analgesic agents without gastric disturbance, structurally simple cyclooxygenase-1 (COX-1) inhibitors with a benzenesulfonanilide skeleton were designed and synthesized. As a result, compounds 11f and 15a, which possess a p-amino group on the benzenesulfonyl moiety and p-chloro group on the anilino moiety, showed COX-1-selective inhibition. Moreover compound 11f, which is the most potent compound in this study showed more potent analgesic activity than that of aspirin at 30 mg/kg by po. The anti-inflammatory activity and gastric damage, however, were very weak or not detectably different from aspirin. Since the structure of our COX-1 inhibitors are very simple, they may be useful as lead compounds for superior COX-1 inhibitors as analgesic agents without gastric disturbance.
Zheng
Xiaoxia
X
Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.
Oda
Hiroyuki
H
Takamatsu
Kayo
K
Sugimoto
Yukio
Y
Tai
Akihiro
A
Akaho
Eiichi
E
Ali
Hamed Ismail
HI
Oshiki
Toshiyuki
T
Kakuta
Hiroki
H
Sasaki
Kenji
K
D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D000813:Anilides / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001557:Benzenesulfonates / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002351:Carrageenan; D003124:Colorimetry; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005753:Gastric Mucosa / Q000473:pathology; D007202:Indicators and Reagents; D007213:Indomethacin / Q000633:toxicity; D007700:Kinetics; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D051381:Rats; D012756:Sheep; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000473:pathology; D013329:Structure-Activity Relationship
D000700:Analgesics; D000813:Anilides; D001557:Benzenesulfonates; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D002351:Carrageenan; D051545:Cyclooxygenase 1; D007213:Indomethacin