The Quest for Small Molecules as Amyloid Inhibiting Therapies for Alzheimer's Disease

Article type: Review Article

Authors: Amijee, Hozefa | Scopes, David I.C.^{; *}

Affiliations: Senexis Limited, Babraham Research Campus, Cambridge, UK

Correspondence: [*] Corresponding author: David I.C. Scopes, Senexis Limited, Babraham Research Campus, Cambridge CB22 3AT, UK. Tel.: +44 1223 496165; Fax: +44 1223 496161; E-mail: [email protected].

Abstract: Amyloid-β (Aβ) 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 Aβ, and therapeutics which block the generation of toxic Aβ 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 Aβ than with fibrillar forms of the peptide. Thus, blocking the initial stages of Aβ 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.

Keywords: Aggregation, amyloid-β, inhibitor, neurotoxicity, oligomer

DOI: 10.3233/JAD-2009-1044

Journal: Journal of Alzheimer's Disease, vol. 17, no. 1, pp. 33-47, 2009