title: Design and synthesis of highly active Alzheimer's beta-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability.
abstract: Recently, we reported potent and small-sized BACE1 inhibitors KMI-358 and KMI-370 in which the Glu residue is replaced by a beta-N-oxalyl-DAP (l-alpha,beta-diaminopropionyl) residue at the P(4) position. The beta-N-oxalyl-DAP group is important for enhancing BACE1 inhibitory activity, but these inhibitors isomerized to alpha-N-oxalyl-DAP derivatives in solvents. Hence, we used a tetrazole moiety as a bioisostere of the free carboxylic acid of the oxalyl group. KMI-420 and KMI-429, containing a tetrazole ring, showed improved stability and potent enzyme inhibitory activity.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Tooru
authors.initials: T
authors.lastname: Kimura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Shuto
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamada
authors.forename: Naoto
authors.initials: N
authors.lastname: Igawa
authors.forename: Soko
authors.initials: S
authors.lastname: Kasai
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: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D004355:Drug Stability; D010450:Endopeptidases; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C500029:KMI-420; C500030:KMI-429; D009842:Oligopeptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases