Identification of Small Molecule Amyloid Beta Peptide Reducing Agent

Alzheimer s disease AD is a multifactorial heterogeneous and enormously complex disorder characterized by progressive intellectual deterioration Although remarkable advances have been made in unraveling the biological basis of the disease in the last two decades that immense knowledge has not been translated in to successful therapy With the failure of secretase inhibitors at the clinical trials and to pursue a new strategy we reasoned that by increasing soluble APP sAPP a powerful neurotrophic factor derived from APP it may be possible to reverse AD Therefore we developed a novel assay to quantify sAPP based on AlphaLISA technology synthesized new thiazole derivatives and screened them for their effect on sAPP Out of several hits we focused on one compound THPI that robustly increased sAPP levels in the primary screen We validated the role of THPI in increasing sAPP in the secondary and tertiary assays We confirmed that THPI can increase sAPP levels at as low as nM in NT cells human primary neurons and fibroblasts derived from AD patients THPI did not alter the activities of secretases Importantly THPI increased sAPP independent of protein kinase C PKC The active compound THPI was found to have significant toxicity only above M thus giving a therapeutic window of Interestingly THPI robustly increased neurite outgrowth and dendritic arbor in human primary neurons suggesting that increased sAPP may be responsible Most importantly THPI passes through the blood brain barrier Our goal in this proposal is first to validate in vivo safety and pharmacokinetics dynamics PK PD of THPI and its analogs through ADMET characterization We will also make more THPI analogs and identify compounds by SAR and medicinal chemistry optimization with better brain penetration and bioavailability to increase more sAPP levels Second we want to confirm in vivo efficacy in increasing sAPP levels and whether THPI also reduces A amyloid plaques and prevent learning and memory deficits in a mouse model of AD Further we will quantify THPI analog concentrations in the brain by LC MS for correlative comparisons between sAPP levels plaque burden and compound levels It is an innovative promising approach to test a compound that robustly increases a powerful neurotrophic factor sAPP which also significantly reduces A levels with enormous therapeutic implications for AD Alzheimer s disease is a persistent neurodegenerative disorder of elderly characterized clinically by irreversible loss of memory due to accumulation of amyloid beta peptides within the amyloid plaques There is now an urgent need to find disease modifying drugs for Alzheimer s disease because the FDA approved drugs currently available to patients are useful only for temporary symptomatic relief In our preliminary studies we identified a new compound by a library screen as a promising amyloid reducing agent which we now want to test in vivo for its ability to lower amyloid plaque burden and memory deficits