title: beta-Secretase inhibitors: modification at the P4 position and improvement of inhibitory activity in cultured cells.
abstract: Recently, we reported potent and small-sized beta-secretase (BACE1) inhibitors KMI-570 and KMI-684 in which we replaced carboxylic acid groups at the P(1)(') position of KMI-420 and KMI-429, respectively, with tetrazole derivatives as carboxylic acid bioisosteres. These modifications improved significantly BACE1 inhibitory activity and chemical stability. In this study, the acidic tetrazole ring of the P(4) position of KMI-420 and KMI-570, respectively, was replaced with various hydrogen bond acceptor groups. We found BACE1 inhibitor KMI-574 that exhibited potent inhibitory activity in cultured cells as well as in vitro enzymatic assay.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamada
authors.forename: Naoto
authors.initials: N
authors.lastname: Igawa
authors.forename: Hayato
authors.initials: H
authors.lastname: Ikari
authors.forename: Zyta
authors.initials: Z
authors.lastname: Ziora
authors.forename: Jeffrey-Tri
authors.initials: JT
authors.lastname: Nguyen
authors.forename: Abdellah
authors.initials: A
authors.lastname: Yamani
authors.forename: Koushi
authors.initials: K
authors.lastname: Hidaka
authors.forename: Tooru
authors.initials: T
authors.lastname: Kimura
authors.forename: Kazuki
authors.initials: K
authors.lastname: Saito
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Maiko
authors.initials: M
authors.lastname: Ebina
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002264:Carboxylic Acids / Q000737:chemistry; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry*; D004952:Esters / Q000737:chemistry; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013777:Tetrazoles / Q000737:chemistry
chemical_list: D002264:Carboxylic Acids; D004952:Esters; D011480:Protease Inhibitors; D013777:Tetrazoles; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human