Progress in the development of nonpeptidomimetic BACE 1 inhibitors for Alzheimer's disease.
It is believed that the production and accumulation of beta-amyloid (Abeta) peptide is a critical step to the pathogenesis of Alzheimer's disease (AD). BACE 1 (beta-site APP-cleaving enzyme 1 or beta-secretase), the key enzyme required for generating Abeta from the beta-amyloid precursor protein (APP), is regarded as an ideal target for AD therapeutic drug design. Due to low oral bioavailability, metabolic instability and poor ability to penetrate the central nervous system (CNS) of the existing peptidomimetic inhibitors, researchers have paid more attention to the development of nonpeptidomimetic inhibitors in recent years. A number of drug screening approaches and technologies have been used to identify novel nonpeptidomimetic BACE 1 inhibitors. This review mainly focuses on the recent developments in structure-based design and synthesis of the nonpeptidomimetic BACE 1 inhibitors.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Wen-Hai
WH
Huang
Rong
R
Sheng
Yong-Zhou
YZ
Hu
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000008:administration & dosage* / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human