title: Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation.
abstract: A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. shaun_stauffer@merck.com
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Stanton
authors.forename: Alison R
authors.initials: AR
authors.lastname: Gregro
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Steinbeiser
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Shaffer
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Rittle
authors.forename: Dennis
authors.initials: D
authors.lastname: Collusi
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Beth L
authors.initials: BL
authors.lastname: Pietrak
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Hochman
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D016367:Baculoviridae / Q000187:drug effects / Q000201:enzymology; D001682:Biological Availability; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D009536:Niacinamide / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009536:Niacinamide; C027681:isonicotinamide; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human