title: Design of pentapeptidic BACE1 inhibitors with carboxylic acid bioisosteres at P1' and P4 positions.
abstract: We previously reported potent BACE1 inhibitors KMI-420 and KMI-570 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. Acidic moieties at the P(1)(') and P(4) positions of KMI inhibitors are thought to be unfavorable in terms of membrane permeability across the blood-brain barrier. Herein, we replaced acidic moieties at the P(4) position with hydrogen bond accepting groups and acidic moieties at the P(1)(') position with less acidic and similar molecular-size moieties (carboxylic acid or tetrazole bioisosteres). These inhibitors exhibited improved BACE1 inhibitory activities and a thorough quantitative structure-activity relationship study was performed.
authors.affiliation: Department of Medicinal Chemistry, Centre Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto 607-8412, Japan.
authors.forename: Harichandra D
authors.initials: HD
authors.lastname: Tagad
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamada
authors.forename: Jeffrey-Tri
authors.initials: JT
authors.lastname: Nguyen
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamada
authors.forename: Hamdy
authors.initials: H
authors.lastname: Abdel-Rahman
authors.forename: Abdellah
authors.initials: A
authors.lastname: Yamani
authors.forename: Ayaka
authors.initials: A
authors.lastname: Nagamine
authors.forename: Hayato
authors.initials: H
authors.lastname: Ikari
authors.forename: Naoto
authors.initials: N
authors.lastname: Igawa
authors.forename: Koushi
authors.initials: K
authors.lastname: Hidaka
authors.forename: Youhei
authors.initials: Y
authors.lastname: Sohma
authors.forename: Tooru
authors.initials: T
authors.lastname: Kimura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002264:Carboxylic Acids / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry
chemical_list: D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; C500029:KMI-420; C551971:KMI-570; D009842:Oligopeptides; D013844:Thiazoles; D014230:Triazoles; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human