title: Structure-activity relationship study of BACE1 inhibitors possessing a chelidonic or 2,6-pyridinedicarboxylic scaffold at the P(2) position.
abstract: We have previously reported potent substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. While these inhibitors exhibited potent activities in enzymatic and cellular assays (KMI-429 in particular inhibited Aβ production in vivo), these inhibitors contained some natural amino acids that seemed to be required to improve enzymatic stability in vivo and permeability across the blood-brain barrier, so as to be practical drug. Recently, we synthesized non-peptidic and small-sized BACE1 inhibitors possessing a heterocyclic scaffold at the P2 position. Herein we report the SAR study of BACE1 inhibitors possessing this heterocyclic scaffold, a chelidonic or 2,6-pyridinedicarboxylic moiety.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima, Chuo-ku, Kobe 650-8586, Japan; Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. Electronic address: pynden@gmail.com.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Diganta
authors.initials: D
authors.lastname: Sarma
authors.affiliation: Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohta
authors.affiliation: Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Moe
authors.initials: M
authors.lastname: Yamasaki
authors.affiliation: Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Koushi
authors.initials: K
authors.lastname: Hidaka
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Meguro-ku, Tokyo 153-8902, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima, Chuo-ku, Kobe 650-8586, Japan; Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan; Laboratory of Peptide Science, Nagahama Institute of Bio-Science and Technology, Tamura-cho, Nagahama 526-0829, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D010848:Picolinic Acids; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011714:Pyrans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010848:Picolinic Acids; D011714:Pyrans; D011725:Pyridines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C046884:chelidonic acid; C004860:dipicolinic acid
keywords: Alzheimer’s disease; BACE1; BACE1 inhibitor; β-Secretase