title: Synthesis and biological evaluation of analogues of a novel inhibitor of beta-amyloid secretion.
abstract: A drug library of 17,200 compounds was screened to select small molecules that inhibit the secretion of amyloid beta peptide (Abeta), the major component of Alzheimer disease senile plaques, from a human neuronal cell line. Twenty-nine hits were validated that decreased Abeta secretion by >40% at 10 microM, for a 0.17% hit rate. A lead hit was selected for further study based on its activity and low cytotoxicity, and it was found to inhibit Abeta secretion through activation of the alpha-secretase pathway. Twenty-four commercially available and 53 synthesized analogues were analyzed for activity. Selected analogues were evaluated for biological stability by incubation with hepatoma cells and for transcellular permeability using Caco-2 cell monolayers. The analogue with the best permeability was evaluated in 2-month old amyloid precursor protein transgenic mice and found to acutely reduce cerebral Abeta levels by 40% after a single iv administration.
authors.affiliation: Department of Cell Biology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
authors.forename: Enakshi
authors.initials: E
authors.lastname: Chakrabarti
authors.forename: Subrata
authors.initials: S
authors.lastname: Ghosh
authors.forename: Sushabhan
authors.initials: S
authors.lastname: Sadhukhan
authors.forename: Lawrence
authors.initials: L
authors.lastname: Sayre
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Tochtrop
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002463:Cell Membrane Permeability; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C551623:2,6-dichloro-N-(2-(3-methylbenzylsulfanyl)ethyl)benzamide; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001549:Benzamides; D013440:Sulfides