Current status and perspectives on the development of therapeutic agents for Alzheimer's disease

Abstract

Acetylcholinesterase inhibitors have beneficial effects to improve the cognitive impairment in patients with mild to moderate Alzheimer's disease (AD). In addition, a channel blocker of N-methyl-D-aspartate receptor, memantine hydrochloride, was approved as a therapeutic agent for patients with moderate to severe AD in both EU countries in 2002 and USA in 2003, while the clinical development is still ongoing in Japan. In contrast, the pharmacotherapy for a prime cure against AD is not available in the market, although there has been a worldwide search for novel compounds. The most plausible mechanism for the treatment of AD is the reduction of the amyloid β-peptide (Aβ) plaques, one of the pathological markers of Aβ, in the brain. For this purpose, the inhibitors of β-secretase and γ-secretase, which cleave amyloid precursor protein (APP) to release Aβ, has been developed to interfere with APP processing. The β-sheet breaker and metal chelators for the breakdown of aggregated Aβ have also been synthesized as well as the immunotherapeutic approach using Aβ vaccine. On the other hand, some nonsteroidal anti-inflammatory drugs, such as ibuprofen and sulindac, noncompetitively inhibited Aβ production but not Notch cleavage. The development of Aβ-lowering drugs is highly expected for the treatment of AD.