title: Design, synthesis and evaluation of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives as BACE-1 inhibitors.
abstract: Three series of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as β-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC50 value of 9.9 μΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK) and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) model.
authors.affiliation: ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Shihao
authors.initials: S
authors.lastname: Shangguan
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Liao
authors.forename: Haiping
authors.initials: H
authors.lastname: Yu
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Wenhai
authors.initials: W
authors.lastname: Huang
authors.forename: Haihong
authors.initials: H
authors.lastname: Hu
authors.forename: Lushan
authors.initials: L
authors.lastname: Yu
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
authors.forename: Rong
authors.initials: R
authors.lastname: Sheng
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010539:Permeability; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C583172:N-(3-(2-amino-6H-1,3,4-thiadiazin-5-yl)-4-(benzyloxy)phenyl)-1-naphthamide hydrobromide; D009281:Naphthalenes; D011480:Protease Inhibitors; D013829:Thiadiazines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human