title: Novel BACE1 inhibitors with a non-acidic heterocycle at the P1' position.
abstract: We have reported potent peptidic and non-peptidic BACE1 inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. However, our potent inhibitors possess a tetrazole ring at the P1' position. It is desirable that central nervous system (CNS) drugs do not possess an acidic moiety. In this study, we synthesized non-acidic BACE1 inhibitors with heterocyclic derivatives at the P1' position. KMI-1764 (27) exhibited potent inhibitory activity (IC50=27nM). Interestingly, these non-acidic inhibitors tended to follow the quantitative structure-activity relationship (QSAR) equation and interacted with BACE1-Arg235 in the binding model.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamada
authors.forename: Jeffrey-Tri
authors.initials: JT
authors.lastname: Nguyen
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001549:Benzamides; D006571:Heterocyclic Compounds; C000588461:N1-(4-(5-bromo-1,3,4-thiadiazol-2-ylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-5-(N-methylmethanesulfonamido)-N3-(1-phenylethyl)isophthalamide; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D013830:Thiadiazoles; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer’s disease; Hydroxymethylcarbonyl isostere; Non-acidic inhibitor; Quantitative structure–activity relationship; β-Secretase