title: P2'-truncated BACE-1 inhibitors with a novel hydroxethylene-like core.
abstract: Highly potent BACE-1 protease inhibitors derived from a novel hydroxyethylene-like core structure were recently developed by our group using X-ray crystal structure data and molecular modelling. In a continuation of this work guided by molecular modelling we have explored a truncated core motif where the P2' amide group is replaced by an ether linkage resulting in a set of alkoxy, aryloxy and alkylaryl groups, with the overall aim to reduce molecular weight and the number of amide bonds to increase permeability and bestow the inhibitors with drug-like features. The most potent of these inhibitors displayed a BACE-1 IC(50) value of 140 nM. The synthesis of these BACE-1 inhibitors utilizes readily available starting materials, furnishing the target compounds in good overall yields.
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.
authors.forename: Jenny Adrian
authors.initials: JA
authors.lastname: Meredith
authors.forename: Catarina
authors.initials: C
authors.lastname: Björklund
authors.forename: Hans
authors.initials: H
authors.lastname: Adolfsson
authors.forename: Katarina
authors.initials: K
authors.lastname: Jansson
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: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D005030:Ethylenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D005030:Ethylenes; D011480:Protease Inhibitors; C067254:hydroxyethylene; D016282:Aspartic Acid Endopeptidases