chf-5074 and Amyloidosis

Hereditary amyloid polyneuropathy is a type of protein misfolding disease. Transthyretin (TTR) is a homotetrameric serum protein and TTR tetramer dissociation is the limiting step in amyloid fibril formation. Thus, prevention of TTR dissociation is a promising therapeutic approach and some TTR stabilizers have been approved for the treatment of TTR amyloidosis. CSP-1103 (CHF5074) is a non-steroidal anti-inflammatory derivative that lacks cyclooxygenase inhibitory activity. In vitro, CSP-1103 stabilizes the TTR tetramer by binding to the thyroxine (T4) binding site. We have previously shown that serum TTR levels were increased by oral CSP-1103 administration through stabilization of TTR tetramers in humanized mice at both the Ttr locus and the Rbp4 locus. To determine whether CSP-1103 stabilizes TTR tetramers in humans, multiple CSP-1103 oral doses were administered for two weeks to 48 healthy human volunteers in a double-blind, placebo-controlled, parallel-group study. CSP-1103 treatment stabilized TTR tetramers in a dose-dependent manner under normal or denaturing stress conditions, thereby increasing serum TTR levels. Preincubation of serum with CSP-1103 or diflunisal in vitro increased the TTR tetramer stability. Computer simulation analysis revealed that the binding affinities of CSP-1103 with TTR at pH 7.0 were similar to those of tafamidis, thus confirming that CSP-1103 has potent TTR-stabilizing activity.

Topics: Amyloidosis; Cyclopropanes; Flurbiprofen; Genetic Diseases, Inborn; Humans; Prealbumin; Thyroxine

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 Aβ(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 Aβ(1-42) at higher concentration, SALA activity was observed at low concentrations (≤1 μM): both Aβ(1-42) and the ratio of Aβ(1-42)/Aβ(1-40) 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.

Topics: Amyloid beta-Peptides; Amyloidosis; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Tumor; Humans; Mice; Neurons; Nitrates; Small Molecule Libraries