title: Substituted organosiloxanes as potential therapeutics for treatment and prevention of neurodegenerative diseases.
abstract: Extensive testing of hydrolysates of commercially available organosilanes has identified a number of bifunctional organosiloxane compounds that show potential as therapeutics for treatment of diseases characterized by amyloid deposition such as Alzheimer's disease (AD). All of these compounds protect from and/or reverse the metal-induced aggregation of amyloid Abeta(1-42) peptide in dynamic light scattering (DLS) assays in trifluoroethanol (TFE) solutions, protect from and/or reverse the metal-induced loss of alpha-helical structure in TFE solutions of amyloid Abeta(1-42) as measured by circular dichroism (CD), and are able to cross blood-brain barrier models at rates above background using Caco-2 and MDCK cell permeation assays. Based on these studies, we conclude that members of this class of bifunctional organosiloxanes are promising candidates for testing in treatment and/or prevention of AD and other diseases characterized by amyloid deposition.
authors.affiliation: GrenPharma LLC, 415 South St., MS 015, Waltham, MA 02454, USA.
authors.forename: Orrie M
authors.initials: OM
authors.lastname: Friedman
authors.forename: Paul
authors.initials: P
authors.lastname: Matsudaira
authors.forename: Arthur H
authors.initials: AH
authors.lastname: Reis
authors.forename: Neil
authors.initials: N
authors.lastname: Simister
authors.forename: Ivan
authors.initials: I
authors.lastname: Correia
authors.forename: David
authors.initials: D
authors.lastname: Kew
authors.forename: Julie Y
authors.initials: JY
authors.lastname: Wei
authors.forename: Thomas
authors.initials: T
authors.lastname: Pochapsky
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects; D002942:Circular Dichroism / Q000379:methods; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000517:prevention & control*; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism; D012833:Siloxanes / Q000627:therapeutic use*; D014270:Trifluoroethanol / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012833:Siloxanes; C075222:amyloid beta-protein (1-42); D014270:Trifluoroethanol