Design and optimization of disease altering drugs for Alzheimer's disease.

There are no "disease stabilizing" drugs available for the treatment of Alzheimer's Disease [AD]. The only drugs currently available in Canada for the treatment of AD are donepezil, galantamine, rivastigmine and memantine. In general, these drugs are cholinesterase enzyme inhibitors which afford only limited symptomatic improvement. There are no drugs that actually affect the natural history of AD as a disease entity. Rather than targeting the cholinesterase enzyme (similar to donepezil or rivastigmine), disease stabilizing agents must target different receptors - receptors which play a role in disease progression and causation. A wealth of current research suggests that B-amyloid is a protein which may function as such a receptor. B-Amyloid is a protein found in significant concentrations in the brains of people with AD. Aggregates of B-amyloid are toxic to brain, causing loss of brain cells and ultimately dementia. In this research, we will design drugs which bind to B-amyloid and thereby reduce or even eliminate its toxicity. This is an attempt to design a disease stabilizing drug. The design of this drug will be achieved using state of the art computer assisted molecular design strategies. Using molecular modelling and computer graphics, molecules capable of binding to a portion of the B-amyloid protein will be designed. The design process will also take into consideration the need for this drug to be able to cross the blood brain barrier and enter the brain. Approximately 100 of these molecules will be designed and synthesized using standard techniques of synthetic organic chemistry. Finally, their ability to bind to a portion of B-amyloid protein will be assessed. The long term goal of this research is to discover a new class of drugs for AD and to identify a prototype drug in this new class.