title: SAR of tertiary carbinamine derived BACE1 inhibitors: role of aspartate ligand amine pKa in enzyme inhibition.
abstract: The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. hemaka_rajapakse@merck.com
authors.forename: Hemaka A
authors.initials: HA
authors.lastname: Rajapakse
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Lindsley
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Young
authors.forename: Phung L
authors.initials: PL
authors.lastname: Ngo
authors.forename: M Katherine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Shi
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: Katherine
authors.initials: K
authors.lastname: Tugusheva
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kuo
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Samuel
authors.initials: S
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000588:Amines / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001224:Aspartic Acid / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human