The Activity Wall in Alzheimer's drug discovery: When potency optimization reaches its limits

Modern drug discovery attrition is often attributed to biological complexity or target invalidation. However, a core obstacle may lie in the industry's asymmetric focus on maximizing binding affinity at the expense of holistic molecular quality, driven by a pervasive potency bias. This produces overengineered leads that collide with an 'Activity Wall', defined here as the multifactorial barrier that prevents chemical analogs from being optimized indefinitely, in which further affinity gains cease to translate into therapeutic success. By exploring chemical space through scaffold-based constellation plots and ligand lipophilic efficiency, we show how structural modifications improve potency primarily via lipophilicity inflation within established scaffolds. This is illustrated by analyzing small-molecule inhibitors of two key Alzheimer's targets: beta-site APP cleaving enzyme 1 and the Tau protein.