The quest for small molecules as amyloid inhibiting therapies for Alzheimer's disease

Abstract

Amyloid-beta (Abeta) peptide is one of the most promising targets for the development of new therapies for Alzheimer's disease (AD). A growing body of evidence suggests a key pathogenic role for soluble oligomers of Abeta, and therapeutics which block the generation of toxic Abeta assemblies may provide successful new treatments for AD. This is therapeutically attractive because the aggregation process is believed to be an exclusively pathological event and therefore compounds targeting this mechanism are more likely to have an acceptable safety profile. A number of studies have shown that AD severity correlates more closely with soluble oligomeric forms of Abeta than with fibrillar forms of the peptide. Thus, blocking the initial stages of Abeta aggregation with small molecules could hold considerable promise as an entry to new therapies for AD. The rapid development in our understanding of toxic amyloid assemblies now provides fresh impetus for this interesting approach, and this review assesses the status of drug development in this area. Recent progress with clinical studies and highlights of new structural series that are showing promise in the discovery/pre-clinical phase are discussed.