Inhibition of Amyloidogenesis by Nonsteroidal Anti-inflammatory Drugs and Their Hybrid Nitrates

Abstract

Poor blood-brain barrier penetration of non-steroidal 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 analogs were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogs were obtained with enhanced anti-inflammatory and anti-amyloidogenic properties compared to 1, however, esterification led to elevated Aβ1–42 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 Aβ1–42 at higher concentration, SALA activity was observed at low concentrations (≤ 1 µM): both Aβ1–42 and the ratio of Aβ1–42/Aβ1–40 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 towards a clinically useful SALA.

Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review

“…By contrast, its ester analogs 17 and 18 (Figure 16), are considered to be NO-releasing prodrugs of indomethacin, due to the observed fast hydrolysis of the ester linkages in these molecules [66,67]. An additional example is the nitrate-containing amide of flurbiprofen 19 that was synthesized and tested as a metabolically more stable analog of 20 ; both compounds are effective inhibitors of amyloidogenesis [68]. …”

Enantioselective fluorination of α-branched aldehydes and subsequent conversion to α-hydroxyacetals via stereospecific C–F bond cleavage

“…First, allyl fluorides 8 were synthesized by Horner–Wadsworth–Emmons reaction of α-fluoroaldehydes 4 in good yield. Next, fluorohydrine 5j was oxidized to carboxylic acid 9 , 13 which is a fluorinated analogue of a non-steroidal anti-inflammatory agent, flurbiprofen.…”

New Functions of Old Drugs: Aureolic Acid Group of Anti-Cancer Antibiotics and Non-Steroidal Anti-Inflammatory Drugs

“…In Fig. To overcome this difficulty, hybrid nitrates as NO-donor NSAID (NO-NSAID) are being designed as selective amyloid lowering agents [141]. [137,138].…”