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.