title: Rational design and synthesis of selective BACE-1 inhibitors.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Brady
authors.forename: Satendra
authors.initials: S
authors.lastname: Singh
authors.forename: Ming Chih
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.forename: Victor M
authors.initials: VM
authors.lastname: Garsky
authors.forename: Michael
authors.initials: M
authors.lastname: Bogusky
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Daria
authors.initials: D
authors.lastname: Hazuda
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
mesh_terms: 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
chemical_list: 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