As shown in Figure 5, dose responsive decreases in Ab38 and Ab42 were observed

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 As shown in Figure 5, dose responsive decreases in Ab38 and Ab42 were observed  Empty As shown in Figure 5, dose responsive decreases in Ab38 and Ab42 were observed

Post  zq123456 on Tue May 20, 2014 5:35 am

Interestingly, despite equipotent inhibition of APP and Notch processing by gamma secretase, sulfones are reported to be well tolerated at 3 mg kg dose in a three month small molecule treatment study in the Tg2576 mouse model, although higher doses were not reported. In a similar vein, whereas potent piperdine containing sulfonamide GSI have also been described, APP selectivity has only been reported following incorporation of a pyra zole substituent into the piperdine sulfonamide core . The molecular basis of sulfonamide based GSIs APP selectivity remains to be fully elucidated. We have reported that one contributor of selectivity may be the more potent inhibition of PS1 gamma secretase com pared with PS2 gamma secretase by sulfonamides.

Consistent with this finding, ELN475516 is a five fold more selective Lenalidomide 分子量 PS1 gamma secretase inhibitor relative to PS2 gamma secretase . Site directed muta genesis studies have identified select residues in PS1 which affect AICD processing from APP without affect ing NICD production from Notch, supporting the potential for modulating cleavage by this enzyme in a selective manner. These observations, combined with substituted cysteine accessibility mutagenesis to more precisely map inhibitor binding residues, offer an avenue to further characterize the biochemical basis of APP selectivity. In summary, the in vivo selectivity of ELN475516 from a mouse seven day safety model cor roborates the improved selectivity estimated for this compound in the cellular SNC assay, confirming APP selective inhibition of gamma secretase in vivo by this novel pyrazolylazabicyclo nonane sulfonamide.

ELN475156 represents a validated foundation for further lead optimization to discover APP selective second gen eration GSIs with improved safety and drug like proper ties suitable for chronic AD therapy . Conclusions Our results showing discordance in reduction of brain Ab between PDAPP and wild type FVB mice following treatment with ELN318463 highlight the importance of evaluating GSIs オーダー LY2603618 for potency and selectivity in non trans gene models of Alzheimers disease. The in vitro and in vivo selectivity of ELN475516 demonstrates that dis covery of APP selective GSIs is feasible, and that APP selective GSIs offer potentially safer candidates as thera peutics for Alzheimers disease. Alzheimers disease is a severe neurodegenerative disease that is defined by two pathological features, amyloid plaques and neurofibrillary tangles.

Because amyloid plaques appear before the onset of clinically defined dementia symptoms, neurodegeneration and subsequent cognitive impairment are hypothesized to be a downstream consequence of b amyloid peptide dysregulation . Ab peptides are small fragments cleaved from a much larger integral membrane protein, the amyloid precursor protein . In the AD cascade, APP is cleaved initially by b secretase, leaving the C99 fragment in the membrane, which is then cleaved by gamma secretase, an aspartyl protease com plex . Gamma secretase continues to make sequen tial cleavages every three to four amino acids, resulting in Ab fragments ranging in size from 49 to fewer than 34 amino acids .


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