Rational design and synthesis of selective BACE-1 inhibitors.
An effective approach for enhancing the selectivity of beta-site amyloid precursor protein cleaving enzyme (BACE 1) inhibitors is developed based on the unique features of the S1' pocket of the enzyme. A series of low molecular weight (<600) compounds were synthesized with different moieties at the P1' position. The selectivity of BACE 1 inhibitors versus cathepsin D and renin was enhanced 120-fold by replacing the hydrophobic propyl group with a hydrophilic propionic acid group.
Brady
Stephen F
SF
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Singh
Satendra
S
Crouthamel
Ming Chih
MC
Holloway
M Katharine
MK
Coburn
Craig A
CA
Garsky
Victor M
VM
Bogusky
Michael
M
Pennington
Michael W
MW
Vacca
Joseph P
JP
Hazuda
Daria
D
Lai
Ming-Tain
MT
D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D015195:Drug Design; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D008970:Molecular Weight; D011422:Propionates / Q000737:chemistry; D013379:Substrate Specificity; D000092502:Renin Inhibitors
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002402:Cathepsin D; D010450:Endopeptidases; D004791:Enzyme Inhibitors; D011422:Propionates; D000092502:Renin Inhibitors; C509280:BACE1 protein, human; C029658:propionic acid