Drug Design and Discovery in Alzheimer’s Disease

Republished Version of Frontiers in Drug Design and Discovery Volume 6

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Towards Small Molecules as Therapies for Alzheimer’s Disease and Other Neurodegenerative Disorders

Pp. 199-290 (92)

Omar Aziz, Roland W. Bürli, David F. Fischer, Julie Frearson and Michael D. Wall

Abstract

Neurodegenerative diseases caused by hereditary or idiosyncratic neuronal dysfunction share some phenotypic commonalities. Intracellular aggregation of proteins, metal dyshomeostasis, generic loss of synaptic connectivity all lead to gradual decline of cognitive or motor neuronal function as patients descend into a clinically symptomatic state. Though significant progress has been made in our understanding of neurological disorders in the past decade, it has yet to translate into therapeutic advancements in disease treatment.

We have chosen to focus this review on Alzheimer’s disease (AD) to highlight the main disease modifying mechanisms shared in common with the Huntington’s (HD) and Parkinson’s disease (PD) phenotypes, specifically, the aggregation of amyloid-β (Aβ) phospho-tau (p-tau), mutant huntingtin (mHtt) and α -synuclein (α-syn) proteins, respectively. We highlight a number of approaches used in pre-clinical drug discovery to identify clinical tools. In addition, we describe a number of less explored alternative hypotheses which have demonstrated good (pre)clinical evidence for a potential therapeutic intervention.

In particular, for AD, we will review the main concepts which have driven drug discovery research in the recent past and for each molecular target, we summarize a rationale and available validation data with commentary on relevant chemical matter and structural biology, then discuss advanced pre-clinical and clinical compounds.

Keywords:

Alzheimer’s disease, amyloid-β, autophagy, Huntington’s disease, lewy bodies, mutant huntingtin, neurodegeneration, Parkinson’s disease, physiochemical properties, pre-clinical drug discovery, reactive oxygen species, α-synuclein, tau.

Affiliation:

BioFocus; Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, UK.