title: Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human beta-secretase.
abstract: The design and synthesis of a novel series of potent and cell permeable peptidomimetic inhibitors of the human beta-secretase (BACE) are described. These inhibitors feature a hydroxyethyl secondary amine isostere and a novel aromatic ring replacement for the C-terminus. The crystal structure of BACE in complex with this hydroxyethyl secondary amine isostere inhibitor is also presented.
authors.affiliation: Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Maillard
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Benson
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Moon
authors.forename: Shumeye
authors.initials: S
authors.lastname: Mamo
authors.forename: Michael
authors.initials: M
authors.lastname: Bienkowski
authors.forename: Alfredo G
authors.initials: AG
authors.lastname: Tomasselli
authors.forename: Danielle D
authors.initials: DD
authors.lastname: Woods
authors.forename: D Bryan
authors.initials: DB
authors.lastname: Prince
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Paddock
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Emmons
authors.forename: John A
authors.initials: JA
authors.lastname: Tucker
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dappen
authors.forename: Louis
authors.initials: L
authors.lastname: Brogley
authors.forename: Eugene D
authors.initials: ED
authors.lastname: Thorsett
authors.forename: Nancy
authors.initials: N
authors.lastname: Jewett
authors.forename: Sukanto
authors.initials: S
authors.lastname: Sinha
authors.forename: Varghese
authors.initials: V
authors.lastname: John
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D016564:Amyloid beta-Protein Precursor; C518309:N-(1-(3,5-difluorobenzyl)-2-hydroxy-3-(3-iodobenzylamino)propyl)-5-methyl-N',N'-dipropylisophthalamide; D010455:Peptides; D010795:Phthalic Acids; D053829:Amyloid Precursor Protein Secretases