Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor.
Although cyclooxygenase-1 (COX-1) inhibition is thought to be a major mechanism of gastric damage by nonsteroidal anti-inflammatory drugs (NSAIDs), some COX-1-selective inhibitors exhibit strong analgesic effects without causing gastric damage. However, it is not clear whether their analgesic effects are attributable to COX-1-inhibitory activity or other bioactivities. Here, we report that N-(5-amino-2-pyridinyl)-4-(trifluoromethyl)benzamide ( 18f, TFAP), which has a structure clearly different from those of currently available COX-1-selective inhibitors, is a potent COX-1-selective inhibitor (COX-1 IC 50 = 0.80 +/- 0.05 microM, COX-2 IC 50 = 210 +/- 10 microM). This compound causes little gastric damage in rats even at an oral dose of 300 mg/kg, though it has an analgesic effect at as low a dose as 10 mg/kg. Our results show that COX-1-selective inhibitors can be analgesic agents without causing gastric damage.
Kakuta
Hiroki
H
Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan. kakuta@pharm.okayama-u.ac.jp
Zheng
Xiaoxia
X
Oda
Hiroyuki
H
Harada
Shun
S
Sugimoto
Yukio
Y
Sasaki
Kenji
K
Tai
Akihiro
A
D000631:Aminopyridines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013055:Spectrophotometry, Infrared; D013270:Stomach / Q000187:drug effects*
D000631:Aminopyridines; D001549:Benzamides; D016861:Cyclooxygenase Inhibitors; C550711:N-(5-amino-2-pyridinyl)-4-trifluoromethylbenzamide; D051545:Cyclooxygenase 1