Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors

Ryosuke Fukai, Xiaoxia Zheng, Kazunori Motoshima, Hiroki Kakuta

Research output: Contribution to journalReview articlepeer-review

4 Citations (Scopus)


Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve physical and mental pain, and to improve patients' quality of life. However, stomach irritation is a major side effect. Most NSAIDs inhibit cyclooxygenases (COXs), and inhibition of COX-1 on the stomach mucous membrane is thought to be responsible for the gastric disturbance. Consequently, development efforts have focused on COX-2-selective inhibitors, while COX-1-selective inhibitors have been rather neglected. Subsequently, however, it was shown that inhibition of either COX-1 or COX-2 alone does not induce gastric damage. Therefore, we have developed the COX-1-selective inhibitor N-(4-aminophenyl)-4- trifluoromethylbenzamide (TFAP), which shows analgesic activity without causing gastric damage. However, metabolism of TFAP generates a colored metabolite, resulting in red-purple coloration of urine after administration. In addition, the analgesic activity of TFAP is weaker than that of indomethacin. Thus, we designed a series of new COX-1-selective inhibitors, the 5-amino-2-ethoxy-N- (substituted)benzamide (ABEX) series, in order to avoid formation of the colored metabolite by modifying the diaminopyridine skeleton. As a result of structural modification and in vitro and in vivo testing of compounds in the ABEX series, we found a novel COX-1-selective inhibitor, 5-amino-2-ethoxy-N-(3- trifluoromethylphenyl)benzamide (ABEX-3TF), which shows better analgesic activity than indomethacin, and does not cause coloration of urine.

Original languageEnglish
Pages (from-to)347-351
Number of pages5
JournalYakugaku Zasshi
Issue number3
Publication statusPublished - Mar 2011


  • Analgesic activity
  • Colored urine
  • Cyclooxygenase-1 (COX-1)
  • Gastric damage

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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