title: Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design.
abstract: β-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-β peptides, is an attractive target for the treatment of Alzheimer's disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 μM to 27 μM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors.
authors: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors: N Yi
authors: NY
authors: Mok
authors: James
authors: J
authors: Chadwick
authors: Katherine A B
authors: KA
authors: Kellett
authors: Eva
authors: E
authors: Casas-Arce
authors: Nigel M
authors: NM
authors: Hooper
authors: A Peter
authors: AP
authors: Johnson
authors: Colin W G
authors: CW
authors: Fishwick
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D044482:Benzeneacetamides / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D044482:Benzeneacetamides; D010648:Phenylacetates; D011480:Protease Inhibitors; C012776:biphenylylacetic acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human