title: Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase.
abstract: A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. james_barrow@merck.com
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Rittle
authors.forename: Phung L
authors.initials: PL
authors.lastname: Ngo
authors.forename: ZhiQiang
authors.initials: Z
authors.lastname: Yang
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Munshi
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Eric A
authors.initials: EA
authors.lastname: Price
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Dennis
authors.initials: D
authors.lastname: Colussi
authors.forename: Katherine
authors.initials: K
authors.lastname: Tugusheva
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Abigail
authors.initials: A
authors.lastname: Wolfe
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.forename: Paul
authors.initials: P
authors.lastname: Zuck
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Levorse
authors.forename: Daria
authors.initials: D
authors.lastname: Hazuda
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D048289:Imidazolidines; D010880:Piperidines; D053829:Amyloid Precursor Protein Secretases