The abnormal proteolysis of amyloid precursor protein (APP) causes the deposition of oligomerized Ab plaques. Genetic isoform apolipoprotein E4 (Apoe4) has been shown to be a risk factor for Alzheimer’s disease. We had earlier identified triarylmethylamine analogs as hit to inhibit Apoe in human brain cells. Further modification and optimization led to sulfonamide analogs as second-generation lead molecules. <i>In vitro </i>biological studies exhibited that sulfonamides acted as Abca1 inducer and/or Ldlr agonist in addition to Apoe inhibition in transgenic mouse brain cells. Our preliminary results led us to hypothesize that this ability for Apoe inhibition in conjunction with Abca1 induction/Ldlr agonism has the potential for Ab plaque clearance in diseased mouse brain. Thus, small molecules with such activity profile could potentially benefit in not only understanding the complex mechanism of Alzheimer’s disease, but also in its therapy. Structure-Activity Relationship (SAR) studies are continuing to improve upon efficacy, potency, and selectivity in order to gain a deeper insight.

Development of small molecules to modulate Apoe and Abca1/Ldlr levels for Alzheimer’s therapy

253rd National Meeting (2017)

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