title: Discovery of potent BACE-1 inhibitors containing a new hydroxyethylene (HE) scaffold: exploration of P1' alkoxy residues and an aminoethylene (AE) central core.
abstract: In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1' methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1' pocket by introducing a set of P1' alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1' positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1' positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed K(i) values in the range of 1-20 nM, where the most potent compounds featured small P1' groups. The cathepsin D selectivity which was high for the smallest P1' substituents (P1'=ethoxy, fold selectively >1500) dropped for larger groups (P1'=benzyloxy, fold selectivity of 3). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden.
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: Jimmy
authors.initials: J
authors.lastname: Lindberg
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Sa
authors.initials: S
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*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005030:Ethylenes / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; 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