Inhibition of amyloidogenesis by nonsteroidal anti-inflammatory drugs and their hybrid nitrates

Isaac T. Schiefer, Samer Abdul-Hay, Huali Wang, Michael Vanni, Zhihui Qin, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Poor blood-brain barrier penetration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer's disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogues were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogues were obtained with enhanced anti-inflammatory and antiamyloidogenic properties compared to 1, however, esterification led to elevated A 1-42 levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate CHF5074. Although hybrid nitrates elevated A 1-42 at higher concentration, SALA activity was observed at low concentrations (1 μM): both A1-42 and the ratio of A 42/A1-40 were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds, the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach toward a clinically useful SALA.

Original languageEnglish (US)
Pages (from-to)2293-2306
Number of pages14
JournalJournal of Medicinal Chemistry
Volume54
Issue number7
DOIs
StatePublished - Apr 14 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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