title: Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors.
abstract: This letter describes replacements for the P3 amide moiety present in previously reported tertiary carbinamine macrolactones. Although P-gp efflux issues associated with these amide-macrolactones were solved and full brain penetration was measured in one case, potency was compromised in the process.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. keith_moore2@merck.com
authors.forename: Keith P
authors.initials: KP
authors.lastname: Moore
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Hemaka A
authors.initials: HA
authors.lastname: Rajapakse
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Eric A
authors.initials: EA
authors.lastname: Price
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Nicole T
authors.initials: NT
authors.lastname: Pudvah
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Hochman
authors.forename: Timothy
authors.initials: T
authors.lastname: Allison
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
mesh_terms: D000588:Amines / Q000493:pharmacokinetics*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D008958:Models, Molecular