title: KMI-008, a novel beta-secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-state mimic: design and synthesis of substrate-based octapeptides.
abstract: A novel class of substrate-based beta-secretase (BACE1) inhibitors containing a hydroxymethylcarbonyl (HMC) isostere was designed and synthesized. Phenylnorstatine [(2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid; Pns] was an effective transition-state mimic at the P(1) position. Structure-activity relationships (SARs) of the P(3)-P(3)' positions of BACE1 inhibitors were studied.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Shuto
authors.forename: Soko
authors.initials: S
authors.lastname: Kasai
authors.forename: Tooru
authors.initials: T
authors.lastname: Kimura
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Koushi
authors.initials: K
authors.lastname: Hidaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamada
authors.forename: Saeko
authors.initials: S
authors.lastname: Shibakawa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Hattori
authors.forename: Beata
authors.initials: B
authors.lastname: Szabo
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism*; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: C488219:KMI-008; D009842:Oligopeptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases