title: Gastric tolerability and prolonged prostaglandin inhibition in the brain with a nitric oxide-releasing flurbiprofen derivative, NCX-2216 [3-[4-(2-fluoro-alpha-methyl-[1,1'-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester].
abstract: NCX-2216 [3-[4-(2-fluoro-alpha-methyl-[1,1'-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester] is an NO-releasing flurbiprofen derivative that also contains a ferulic acid (antioxidant) moiety. NCX-2216 has been shown to be effective in reducing beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease. The tolerability of this compound in the stomach and its ability to suppress prostaglandin synthesis in the brain are not known. The purpose of this study was to assess the contribution of nitric oxide (NO) and ferulic acid to the pharmacological properties of NCX-2216 versus flurbiprofen; thus, we compared their gastric tolerability and suppression of prostaglandin synthesis, peripherally and centrally. Oral flurbiprofen produced extensive gastric damage and suppressed gastric prostaglandin synthesis. In contrast, while suppressing prostaglandin production, equimolar doses of NCX-2216 did not cause detectable gastric injury. The NO-releasing moiety of NCX-2216 (but not the ferulic acid moiety) was crucial for the gastric safety of this compound. NCX-2216 substantially inhibited prostanoid synthesis despite not being detectable in plasma and despite producing only low amounts of flurbiprofen in plasma and in the brain. Inhibition of brain prostaglandin synthesis by NCX-2216 (22 mg/kg) persisted for a much longer period of time (up to 48 h) than was seen with flurbiprofen (<or=12 h). These results demonstrate that a single administration of NCX-2216 can produce prolonged suppression of brain prostaglandin synthesis without causing gastric injury. It is likely that an active metabolite of NCX-2216 contributes to the suppression of cyclooxygenase activity. NCX-2216 may represent an attractive alternative to conventional nonsteroidal anti-inflammatory drugs for long-term treatment of a variety of inflammatory disorders, especially those occurring in the central nervous system.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Calgary, Alberta, Canada. wallacej@ucalgary.ca
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
authors.forename: Marcelo N
authors.initials: MN
authors.lastname: Muscará
authors.forename: Gilberto
authors.initials: G
authors.lastname: de Nucci
authors.forename: Stella
authors.initials: S
authors.lastname: Zamuner
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.forename: Piero
authors.initials: P
authors.lastname: del Soldato
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D011448:Prostaglandin Antagonists / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects*
chemical_list: C450321:(3-4-(2-fluoromethyl-(1,1'-biphenyl)-4-acetyloxy)-3-methoxyphenyl)-2-propenoic acid 4-nitrooxy butyl ester; D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D009569:Nitric Oxide; D005480:Flurbiprofen; D011451:Prostaglandin-Endoperoxide Synthases