Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity

Naoki Yamakawa, Koichiro Suzuki, Yasunobu Yamashita, Takashi Katsu, Kengo Hanaya, Mitsuru Shoji, Takeshi Sugai, Tohru Mizushima

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) achieve their anti-inflammatory effect by inhibiting cyclooxygenase activity. We previously suggested that in addition to cyclooxygenase-inhibition at the gastric mucosa, NSAID-induced gastric mucosal cell death is required for the formation of NSAID-induced gastric lesions in vivo. We showed that celecoxib exhibited the most potent membrane permeabilizing activity among the NSAIDs tested. In contrast, we have found that the NSAID rofecoxib has very weak membrane permeabilizing activity. To understand the membrane permeabilizing activity of coxibs in terms of their structure-activity relationship, we separated the structures of celecoxib and rofecoxib into three parts, synthesized hybrid compounds by substitution of each of the parts, and examined the membrane permeabilizing activities of these hybrids. The results suggest that the sulfonamidophenyl subgroup of celecoxib or the methanesulfonylphenyl subgroup of rofecoxib is important for their potent or weak membrane permeabilizing activity, respectively. These findings provide important information for design and synthesis of new coxibs with lower membrane permeabilizing activity.

Original languageEnglish
Pages (from-to)2529-2534
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number8
DOIs
Publication statusPublished - 2014 Apr 15

Fingerprint

Celecoxib
Structure-Activity Relationship
Anti-Inflammatory Agents
Membranes
Gastrointestinal Agents
Pharmaceutical Preparations
Cyclooxygenase 2 Inhibitors
Prostaglandin-Endoperoxide Synthases
Cell death
Gastric Mucosa
rofecoxib
Cell Death
Substitution reactions

Keywords

  • Celecoxib
  • COX-2 selectivity
  • Gastric adverse effect
  • Membrane permeabilization
  • Rofecoxib

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

Cite this

Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity. / Yamakawa, Naoki; Suzuki, Koichiro; Yamashita, Yasunobu; Katsu, Takashi; Hanaya, Kengo; Shoji, Mitsuru; Sugai, Takeshi; Mizushima, Tohru.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 8, 15.04.2014, p. 2529-2534.

Research output: Contribution to journalArticle

Yamakawa, Naoki ; Suzuki, Koichiro ; Yamashita, Yasunobu ; Katsu, Takashi ; Hanaya, Kengo ; Shoji, Mitsuru ; Sugai, Takeshi ; Mizushima, Tohru. / Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 8. pp. 2529-2534.
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