Alzheimer's disease (AD) is a debilitating progressive neurodegenerative condition which results in memory loss, loss of independent function, and ultimately death.  According to the current amyloid cascade hypothesis, the production and accumulation of the toxic soluble oligomers of Abeta1-42 are causal in the cascade of events leading to AD.  Gamma-secretase is one of the two proteases responsible for producing the Abeta peptides, however inhibitors of this enzyme have not advanced to market due to toxicity attributed to inhibition of Notch processing.  Gamma-secretase modulators (GSM's) are compounds which shift the production of Abeta1-42 to shorter, less toxic and less aggregation-prone species such as Abeta1-37 and Abeta1-38, while preserving normal Notch function.  Our labs have advanced a pyrimidine-based, non-NSAID-like, Gamma-secretase modulator into the clinic.  This talk presents our effort to optimize solubility, hERG, CYP3A4, and PXR en route to the discovery of our clinical compound BMS-932481.

Bicyclic pyrimidine modulators of Abeta production for the treatment of Alzheimer's disease

248th National Meeting (2014)

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