title: Synthesis and biological evaluation of loxoprofen derivatives.
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.
authors.affiliation: Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamakawa
authors.forename: Shintaro
authors.initials: S
authors.lastname: Suemasu
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matoyama
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Katsu
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Masami
authors.initials: M
authors.lastname: Otsuka
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizushima
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002463:Cell Membrane Permeability / Q000187:drug effects; D003198:Computer Simulation; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats
chemical_list: C561099:2-(4'-hydroxy-5-((2-oxocyclopentyl)methyl)biphenyl-2-yl)propanoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D010666:Phenylpropionates; C040656:loxoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2