Lee H. Latimer

Therapeutic approaches to Alzheimer’s disease

Several recent advances have provided new insights and possibilities in defining therapeutic targets for Alzheimers disease. Of particular importance is the identification of the beta-secretase enzyme and the demonstration that immunization of a transgenic mouse model of Alzheimers disease with Abeta(1-42) peptide can prevent or alleviate neuropathological features of the disease.

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.

Discovery of a novel [3.2.1] benzo fused bicyclic sulfonamide-pyrazoles as potent, selective and efficacious γ-secretase inhibitors

Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.

P4-330: Substrate concentration dependent inhibition of gamma secretase by novel inhibitors

A 42-induced neurotoxicity and reduce A deposits in the brain of 3xTg-AD mice. Polyclonal as well as 6E10 monoclonal antibodies inhibit neurotoxicity induced by A fibrils, but only the former is relatively potent in reducing toxicity induced by A oligomers. Both antibodies significantly reduce the A plaque burden in 3xTg-AD mice after a single intrahippocampal injection. Conclusions: Thus, anti-A 1-11 antibodies are effective against all pathological forms of the A peptide, including most toxic oligomers, which suggests the potential utility of our novel AD vaccine.