Progress in the discovery of BACE inhibitors.
Dementia caused by Alzheimer's disease is a large medical burden on society in the developed world. Current treatments are largely symptomatic, and there is an urgent need for therapies which can interrupt or reverse the progression of disease. A number of strategies for intervention are being actively pursued; among the most promising is the inhibition of beta-secretase, or BACE. BACE is the enzyme responsible for N-terminal cleavage of the Alzheimer's precursor protein leading to the production of the beta-amyloid peptide. This cascade ultimately leads to the formation of amyloid plaques, one of the hallmark lesions of the disease. It is expected that inhibitors of BACE may therefore serve as an effective disease-modifing therapy for the treatment of AD. This concept has received significant attention by both academics and the pharmaceutical industry. This review focuses on a discussion of the reported structure-activity relationships for inhibitors of this important therapeutic target.
Thompson
Lorin A
LA
Bristol-Myers Squibb Pharmaceutical Research Institute 5 Research Parkway Wallingford, CT 06492, USA. lorin.thompson@bms.com
Bronson
Joanne J
JJ
Zusi
F Christopher
FC
D000544:Alzheimer Disease / Q000188:drug therapy / Q000453:epidemiology; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002626:Chemistry, Pharmaceutical / Q000379:methods / Q000639:trends*; D010450:Endopeptidases / Q000138:chemical synthesis* / Q000627:therapeutic use; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D021281:Quantitative Structure-Activity Relationship
D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human