Synthesis and biological evaluation of loxoprofen derivatives

Naoki Yamakawa, Shintaro Suemasu, Masaaki Matoyama, Ken Ichiro Tanaka, Takashi Katsu, Keishi Miyata, Yoshinari Okamoto, Masami Otsuka, Tohru Mizushima

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12 Citations (Scopus)

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) achieve their anti-inflammatory actions through an inhibitory effect on cyclooxygenase (COX). Two COX subtypes, COX-1 and COX-2, are responsible for the majority of COX activity at the gastrointestinal mucosa and in tissues with inflammation, respectively. We previously suggested that both gastric mucosal cell death due to the membrane permeabilization activity of NSAIDs and COX-inhibition at the gastric mucosa are involved in NSAID-induced gastric lesions. We have also reported that loxoprofen has the lowest membrane permeabilization activity among the NSAIDs we tested. In this study, we synthesized a series of loxoprofen derivatives and examined their membrane permeabilization activities and inhibitory effects on COX-1 and COX-2. Among these derivatives, 2-{4′-hydroxy-5-[(2-oxocyclopentyl)methyl]biphenyl-2-yl}propanoate 31 has a specificity for COX-2 over COX-1. Compared to loxoprofen, oral administration of 31 to rats produced fewer gastric lesions but showed an equivalent anti-inflammatory effect. These results suggest that 31 is likely to be a therapeutically beneficial and safer NSAID.

Original languageEnglish
Pages (from-to)3299-3311
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number11
DOIs
Publication statusPublished - 2011 Jun 1
Externally publishedYes

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Keywords

  • COX-2 specificity
  • Gastric lesions
  • Gastric mucosal cells
  • Loxoprofen
  • Membrane permeabilization

ASJC Scopus subject areas

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

Cite this

Yamakawa, N., Suemasu, S., Matoyama, M., Tanaka, K. I., Katsu, T., Miyata, K., Okamoto, Y., Otsuka, M., & Mizushima, T. (2011). Synthesis and biological evaluation of loxoprofen derivatives. Bioorganic and Medicinal Chemistry, 19(11), 3299-3311. https://doi.org/10.1016/j.bmc.2011.04.050