title: β-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease.
abstract: An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aβ40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aβ40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.
authors.affiliation: Discovery Chemistry, Pharma Research & Early Development, Grenzacherstrasse 124, Basel CH-4070, Switzerland. hans.hilpert@roche.com
authors.forename: Hans
authors.initials: H
authors.lastname: Hilpert
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Guba
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Woltering
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wostl
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pinard
authors.forename: Harald
authors.initials: H
authors.lastname: Mauser
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Mayweg
authors.forename: Mark
authors.initials: M
authors.lastname: Rogers-Evans
authors.forename: Roland
authors.initials: R
authors.lastname: Humm
authors.forename: Daniela
authors.initials: D
authors.lastname: Krummenacher
authors.forename: Thorsten
authors.initials: T
authors.lastname: Muser
authors.forename: Christian
authors.initials: C
authors.lastname: Schnider
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bergadano
authors.forename: David W
authors.initials: DW
authors.lastname: Banner
authors.forename: Remo
authors.initials: R
authors.lastname: Hochstrasser
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.forename: Pascale
authors.initials: P
authors.lastname: David-Pierson
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Alessandra
authors.initials: A
authors.lastname: Polara
authors.forename: Robert
authors.initials: R
authors.lastname: Narquizian
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001923:Brain Chemistry; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005461:Fluorine / Q000737:chemistry; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008958:Models, Molecular; D010078:Oxazines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010078:Oxazines; D005461:Fluorine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse