title: Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core.
abstract: We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxylethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the P1-position. The final inhibitors were optimized using three different amines to provide the residues in the P2'-P3' position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1'-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-1 assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC(50) value of 3.1 nM.
authors.affiliation: Department of Chemistry, Linköping University, SE-581 83 Linköping, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wångsell
authors.forename: Karin
authors.initials: K
authors.lastname: Gustafsson
authors.forename: Ingemar
authors.initials: I
authors.lastname: Kvarnström
authors.forename: Neera
authors.initials: N
authors.lastname: Borkakoti
authors.forename: Michael
authors.initials: M
authors.lastname: Edlund
authors.forename: Katarina
authors.initials: K
authors.lastname: Jansson
authors.forename: Jimmy
authors.initials: J
authors.lastname: Lindberg
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Asa
authors.initials: A
authors.lastname: Rosenquist
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005030:Ethylenes / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005030:Ethylenes; C067254:hydroxyethylene; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human