title: Rapid P1 SAR of brain penetrant tertiary carbinamine derived BACE inhibitors.
abstract: This Letter describes the one pot synthesis of tertiary carbinamine 3 and related analogs of brain penetrant BACE-1 inhibitors via the alkylation of the Schiff base intermediate 2. The methodology developed for this study provided a convenient and rapid means to explore the P1 region of these types of inhibitors, where the P1 group is installed in the final step using a one-pot two-step protocol. Further SAR studies led to the identification of 10 which is twofold more potent in vitro as compared to the lead compound. This inhibitor was characterized in a cisterna magna ported rhesus monkey model, where significant lowering of CSF Abeta40 was observed.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Mary B
authors.initials: MB
authors.lastname: Young
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.forename: Eric A
authors.initials: EA
authors.lastname: Price
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Shi
authors.forename: Katherine
authors.initials: K
authors.lastname: Tugusheva
authors.forename: Marie A
authors.initials: MA
authors.lastname: Holahan
authors.forename: Maria S
authors.initials: MS
authors.lastname: Michener
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.forename: Adam
authors.initials: A
authors.lastname: Simon
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Hemaka A
authors.initials: HA
authors.lastname: Rajapakse
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008253:Macaca mulatta; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010446:Peptide Fragments; D013449:Sulfonamides; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human