title: Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid β-peptides.
abstract: Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aβ following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d.
authors: Department of Global Discovery Chemistry, Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. heinrich.rueeger@novartis.com
authors: Heinrich
authors: H
authors: Rueeger
authors: Rainer
authors: R
authors: Lueoend
authors: Rainer
authors: R
authors: Machauer
authors: Siem Jacob
authors: SJ
authors: Veenstra
authors: Laura Helen
authors: LH
authors: Jacobson
authors: Matthias
authors: M
authors: Staufenbiel
authors: Sandrine
authors: S
authors: Desrayaud
authors: Jean-Michel
authors: JM
authors: Rondeau
authors: Henrik
authors: H
authors: Möbitz
authors: Ulf
authors: U
authors: Neumann
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000737:chemistry*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D001923:Brain Chemistry; D018360:Crystallography, X-Ray; D003500:Cyclization; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013454:Sulfoxides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D013454:Sulfoxides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; BACE-1; Cyclic sulfoxide hydroxyethylamine inhibitors; In vivo reduction of amyloid β-peptides; Inhibitor; Structure based design