title: Design, synthesis, and evaluation of Leu*Ala hydroxyethylene-based non-peptide beta-secretase (BACE) inhibitors.
abstract: With the aim of developing small molecular non-peptide beta-secretase (BACE) inhibitors, Leu*Ala hydroxyethylene (HE) was investigated as a scaffold to design and synthesize a series of compounds. Taking advantage of efficient combinatorial synthesis approaches and molecular modeling, extensive structure-activity relationship (SAR) studies were carried out on the N- and C-terminal residues of the Leu*Ala HE scaffold. Isobutyl amine was found to be an optimal C-cap, and suitable hydroxylalkylamines at the 3-position and nitro or methyl(methylsulfonyl)amine at the 5-position of isophthalamide as the N-terminus could form additional hydrogen bonds with BACE active sites and help improve potency. Many new potent non-peptide BACE inhibitors were identified in this study. Among them, compounds 37 and 44 exhibited excellent enzyme-inhibiting potency, comparable to that of OM99-2, and obvious inhibitory effects in cell-based assay with low molecular weights (<600).
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: Xiao
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Jingya
authors.initials: J
authors.lastname: Li
authors.forename: Lanping
authors.initials: L
authors.lastname: Ma
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Haiping
authors.initials: H
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Zeqiang
authors.initials: Z
authors.lastname: Ma
authors.forename: Beiying
authors.initials: B
authors.lastname: Qiu
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Dingyu
authors.initials: D
authors.lastname: Hu
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D001549:Benzamides / Q000737:chemistry*; D002219:Carbamates / Q000737:chemistry*; D004151:Dipeptides / Q000737:chemistry*; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry / Q000187:drug effects*; D005030:Ethylenes / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D009578:Nitrobenzenes / Q000737:chemistry*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D001549:Benzamides; D002219:Carbamates; D004151:Dipeptides; D005030:Ethylenes; C512504:Leu-Ala hydroxyethylene; C512505:N'-((4S,5S,7R)-7-(isobutylcarbamoyl)-5-hydroxy-2-methyloctan-4-yl)-N-((R)-1-hydroxy-3-methylbutan-2-yl)5-nitrobenzene-1,3-diamide; C512506:N'-((4S,5S,7R)-7-(isobutylcarbamoyl)-5-hydroxy-2-methyloctan-4-yl)-N-((S)-1-hydroxy-3-methylbutan-2-yl)5-(methyl(methylsulfonyl)amine)benzene-1,3-diamide; D009578:Nitrobenzenes; C414614:OM99-2; D009842:Oligopeptides; D010455:Peptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human