Lead Optimization and Lead Evolution of Potent SGSMs for the Treatment of Alzheimer’s Disease

This application outlines a highly focused extension of an NIH-funded Blueprint Neurotherapeutics (BPN) U01 program to create more potent, soluble, brain penetrant, nontoxic small molecules known as soluble gamma-secretase modulators (SGSMs) that act to enhance the activity/processivity of y-secretase, thereby reducing the levels of Aβ₄₂ and to a lesser extent Aβ₄₀ while increasing the levels of shorter Abeta peptides (e.g., Aβ₃₈ and Aβ₃₇)

Our application builds on the previous synthesis of a large number of SGSMs that have been optimized for potency, physicochemical properties, absorption, distribution, metabolism, excretion and toxicity (ADMET), in addition to in vivo pharmacokinetic (PK) and pharmacodynamics (PD) properties. The prior studies were supported through a BPN U01 award that included three years of lead optimization and lead evolution involving structure-activity relationship (SAR), quantitative structure-activity relationship (QSAR) and structure-property relationship (SPR) studies.