Developing ß-secretase inhibitors for treatment of Alzheimer's disease

beta-Secretase (memapsin 2; BACE-1) is the first protease in the processing of amyloid precursor protein leading to the production of amyloid-beta (A beta) in the brain. It is believed that high levels of brain A beta are responsible for the pathogenesis of Alzheimers disease (AD). Therefore, beta-secretase is a major therapeutic target for the development of inhibitor drugs. During the past decade, steady progress has been made in the evolution of beta-secretase inhibitors toward better drug properties. Recent inhibitors are potent, selective and have been shown to penetrate the blood-brain barrier to inhibit A beta levels in the brains of experimental animals. Moreover, continuous administration of a beta-secretase inhibitor was shown to rescue age-related cognitive decline in transgenic AD mice. A small number of beta-secretase inhibitors have also entered early phase clinical trials. These developments offer some optimism for the clinical development of a disease-modifying drug for AD.