Progress toward a practical BACE-1 inhibitor.
Over the last six years, numerous research groups in both academia and industry have synthesized inhibitors of beta-amyloid cleaving enzyme-1 (BACE-1) in the hope of developing a therapy to halt or even reverse the progression of Alzheimer's disease. While several compounds have been demonstrated to be potent in vitro inhibitors of BACE-1, only a small subset of these compounds are able to satisfy other practical considerations essential for the development of a preclinical drug candidate. These considerations include selectivity of the inhibitor toward BACE-1 over other enzymes, cellular activity, and in vivo activity in an animal model. This review will summarize the recent development of BACE-1 inhibitors with particular focus placed on inhibitors that address some of the requirements necessary for a practical drug candidate.
Hills
Ivory D
ID
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. ivory_hills@merck.com
Vacca
Joseph P
JP
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D023421:Models, Animal; D015394:Molecular Structure
D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human