Jay S. Tung

Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: structure-activity relationship of the aryl region.

The structure-activity relationship of the prime region of hydroxyethylamine BACE inhibitors is described. Variation in the aryl linker region with 5- and 6-membered heterocycles provided compounds such as 33 with improved permeability and reduced P-gp liability compared to benzyl amine analog 1.

A series of C-Terminal amino alcohol dipeptide Aβ inhibitors

Potent, small molecule Aβ inhibitors have been prepared that incorporate an alanine core bracketed by an N-terminal arylacetyl group and various C-terminal amino alcohols. The compounds exhibit stereospecific inhibition as demonstrated in an in vitro assay.

Chapter 2. Alzheimer's Disease: Recent Advances on the Amyloid Hypothesis

Publisher Summary The “amyloid hypothesis” postulates that β-amyloid peptide 42 amino acid (Aβ 42 ), in particular, is causal in the Alzheimers disease (AD) process, the most common form of dementia. This hypothesis is supported primarily by genetic evidence from individuals who greatly overproduce Aβ 42 and possess disease-causing mutations in genes coding for either amyloid precursor protein (APP) or the recently discovered presenilin proteins (PS1 or PS2). A growing effort is being directed toward the therapeutic strategies that target the effects of Aβ as treatments for the causes of AD. These strategies are complimentary to symptomatic cognition-improvement therapies based on the acetylcholinesterase (AChE) inhibitors and M1 agonists. The Aβ strategies take three forms described as: (1) disruption of Aβ production from its precursor protein, (2) protection from the neurotoxicity of the Aβ aggregates, and (3) inhibition of the aggregation of Aβ monomer into the neurotoxic aggregates that constitute the plaques. Research in APP processing, Aβ induced neurotoxicity, and Aβ aggregation have reached a level of maturation where clinical evaluation of the “amyloid hypothesis” is anticipated. Recent developments in transgenic mouse models that develop AD pathology are expected to greatly assist the evaluation of potential agents for this devastating disease.