title: Rational design and synthesis of aminopiperazinones as β-secretase (BACE) inhibitors.
abstract: Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.
authors.affiliation: Research Informatics & Integrative Genomics, Calle Jarama 75, Poligono Industrial, Toledo 45007, Spain. gtresade@its.jnj.com
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.forename: Francisca
authors.initials: F
authors.lastname: Delgado
authors.forename: Oscar
authors.initials: O
authors.lastname: Delgado
authors.forename: Harrie
authors.initials: H
authors.lastname: Gijsen
authors.forename: Gregor J
authors.initials: GJ
authors.lastname: Macdonald
authors.forename: Dieder
authors.initials: D
authors.lastname: Moechars
authors.forename: Frederik
authors.initials: F
authors.lastname: Rombouts
authors.forename: Richard
authors.initials: R
authors.lastname: Alexander
authors.forename: John
authors.initials: J
authors.lastname: Spurlino
authors.forename: Michiel
authors.initials: M
authors.lastname: Van Gool
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Vega
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; D053829:Amyloid Precursor Protein Secretases