title: Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1).
abstract: We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 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: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Lindsley
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Young
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: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000814:Aniline Compounds; D010069:Oxadiazoles; D053829:Amyloid Precursor Protein Secretases