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

Ryosuke Fukai, Xiaoxia Zheng, Kazunori Motoshima, Hiroki Kakuta

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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
Volume131
Issue number3
DOIs
Publication statusPublished - Mar 2011

Fingerprint

Cyclooxygenase 1
Stomach
Analgesics
Indomethacin
Anti-Inflammatory Agents
Urine
Cyclooxygenase 2 Inhibitors
Cyclooxygenase 2
Prostaglandin-Endoperoxide Synthases
Skeleton
Pharmaceutical Preparations
Mucous Membrane
Quality of Life
Pain

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors. / Fukai, Ryosuke; Zheng, Xiaoxia; Motoshima, Kazunori; Kakuta, Hiroki.

In: Yakugaku Zasshi, Vol. 131, No. 3, 03.2011, p. 347-351.

Research output: Contribution to journalArticle

Fukai, Ryosuke ; Zheng, Xiaoxia ; Motoshima, Kazunori ; Kakuta, Hiroki. / Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors. In: Yakugaku Zasshi. 2011 ; Vol. 131, No. 3. pp. 347-351.
@article{4b2b0cdf8d874b5ebee0dd1d9ef5c15c,
title = "Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors",
abstract = "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.",
keywords = "Analgesic activity, Colored urine, Cyclooxygenase-1 (COX-1), Gastric damage",
author = "Ryosuke Fukai and Xiaoxia Zheng and Kazunori Motoshima and Hiroki Kakuta",
year = "2011",
month = "3",
doi = "10.1248/yakushi.131.347",
language = "English",
volume = "131",
pages = "347--351",
journal = "Yakugaku Zasshi",
issn = "0031-6903",
publisher = "Pharmaceutical Society of Japan",
number = "3",

}

TY - JOUR

T1 - Significance and creation of novel cyclooxygenase-1 (COX-1) selective inhibitors

AU - Fukai, Ryosuke

AU - Zheng, Xiaoxia

AU - Motoshima, Kazunori

AU - Kakuta, Hiroki

PY - 2011/3

Y1 - 2011/3

N2 - 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.

AB - 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.

KW - Analgesic activity

KW - Colored urine

KW - Cyclooxygenase-1 (COX-1)

KW - Gastric damage

UR - http://www.scopus.com/inward/record.url?scp=79952265579&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952265579&partnerID=8YFLogxK

U2 - 10.1248/yakushi.131.347

DO - 10.1248/yakushi.131.347

M3 - Article

C2 - 21372527

AN - SCOPUS:79952265579

VL - 131

SP - 347

EP - 351

JO - Yakugaku Zasshi

JF - Yakugaku Zasshi

SN - 0031-6903

IS - 3

ER -