Non-Peptide Amyloid Plaque Formation Inhibitors

University Of The Sciences Philadelphia, Philadelphia PA

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): The major biological mechanisms being investigated in Alzheimer's Disease (AD) for therapeutic intervention include increasing acetylcholine (ACh) levels in the brain, anti-oxidants, anti-inflammatory, and hormonal (estrogenic) replacement. Currently, only 5 drugs are FDA approved to treat Alzheimer's disease. Four (4) of these drugs act by increasing ACh levels in the brain mainly by inhibiting acetycholine esterase (AChE), the enzyme that metabolizes ACh. The 5th and latest compound acts as an NMDA receptor antagonist. These compounds reduce the rate of onset of the symptoms for many patients. However, they do not address mechanisms leading to onset or progression of Alzheimer's disease, and are effective for only about 2 years though the average AD patient lives for about 8 years after diagnosis. They also have many significant negative side effects. The other mechanisms described also have many limitations including not addressing mechanism of onset, progression, and many negative side effects. For example, many men may not wish to consume estrogenic compounds since they increase feminine characteristics and are also known to increase risk of some cancers. Chemically, all these compounds belong in several classes, ranging from naturally occurring alkaloids to synthetic steroids. Recent efforts include strategies to reduce or prevent formation of amyloid plaque, a major biomarker in the development and progression of Alzheimer's disease. Our hypothesis is that cage or bicyclic compounds with appropriate functional groups will be potent inhibitors of formation of peptides required for amyloid plaque. We propose to demonstrate this by designing and synthesizing functionalized (amide bioisostere and/or amine) cage (adamantane) and bicyclic (norcamphor and tropane) compounds capable of acting to prevent formation of Abeta40 and/or Abeta42 peptide fragments which are required for amyloid plaque formation. These peptides are produced from sequential proteolytic processing of beta- amyloid precursor protein (APR) by beta- and gamma-secretases. The target compounds were designed to act primarily by inhibiting gamma-secretase activity (directly or through it's modulation) and therefore production of those fragments. This application is relevant to public health as it addresses Alzheimer's disease, an increasing health concern given the increasing elder population. It seeks to study a mechanism leading to Alzheimer's disease. It can form the foundation for discovery and development of new drugs for prevention and/or treatment of Alzheimer's disease. [unreadable] [unreadable]