title: Reductions in beta-amyloid concentrations in vivo by the gamma-secretase inhibitors BMS-289948 and BMS-299897.
abstract: A primary pathological feature of Alzheimer's disease is beta-amyloid (Abeta)-containing plaques in brain and cerebral vasculature. Reductions in the formation of Abeta peptides by gamma-secretase inhibitors may be a viable therapy for reducing Abeta in Alzheimer's disease. Here we report on the effects of two orally active gamma-secretase inhibitors. BMS-289948 (4-chloro-N-(2,5-difluorophenyl)-N-((1R)-{4-fluoro-2-[3-(1H-imidazol-1-yl)propyl]phenyl}ethyl)benzenesulfonamide hydrochloride) and BMS-299897 (4-[2-((1R)-1-{[(4-chlorophenyl)sulfonyl]-2,5-difluoroanilino}ethyl)-5-fluorophenyl]butanoic acid) markedly reduced both brain and plasma Abeta(1-40) in APP-YAC mice with ED(50) values of 86 and 22 mg/kg per os (po), respectively, for BMS-289948, and 30 and 16 mg/kg po, respectively, for BMS-299897. Both compounds also dose-dependently increased brain concentrations of APP carboxy-terminal fragments, consistent with inhibition of gamma-secretase. BMS-289948 and BMS-299897 (100 mg/kg po) reduced brain and plasma Abeta(1-40) rapidly (within 20min) and maximally within 3 h. BMS-299897 also dose-dependently reduced cortical, cerebrospinal fluid (CSF), and plasma Abeta in guinea pigs with ED(50) values of 30 mg/kg intraperitoneally, without affecting CSF levels of alpha-sAPP. The reductions in cortical Abeta correlated significantly with the reductions in both plasma (r(2) = 0.77) and CSF (r(2) = 0.61) Abeta. The decreases in Abeta were apparent at 3 and 6 h post-administration of BMS-299897, but not at 12h. These results demonstrate that BMS-289948 and BMS-299897 are orally bioavailable, functional gamma-secretase inhibitors with the ability to markedly reduce Abeta peptide concentrations in APP-YAC transgenic mice and in guinea pigs. These compounds may be useful pharmacologically for examining the effects of reductions in beta-amyloid peptides in both animal models and in Alzheimer's disease.
authors.affiliation: SIBIA Neurosciences, Inc., 300 S. Coast Blvd, La Jolla, CA 92037, USA. janderson@cypressbio.com
authors.forename: Jeffery J
authors.initials: JJ
authors.lastname: Anderson
authors.forename: Greg
authors.initials: G
authors.lastname: Holtz
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Baskin
authors.forename: Mary
authors.initials: M
authors.lastname: Turner
authors.forename: Blake
authors.initials: B
authors.lastname: Rowe
authors.forename: Bowei
authors.initials: B
authors.lastname: Wang
authors.forename: Maria Z
authors.initials: MZ
authors.lastname: Kounnas
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
authors.forename: Donna
authors.initials: D
authors.lastname: Barten
authors.forename: Kevin
authors.initials: K
authors.lastname: Felsenstein
authors.forename: Ian
authors.initials: I
authors.lastname: McDonald
authors.forename: Kumar
authors.initials: K
authors.lastname: Srinivasan
authors.forename: Ben
authors.initials: B
authors.lastname: Munoz
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000097:blood; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001923:Brain Chemistry / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D010450:Endopeptidases / Q000187:drug effects*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000032:analysis; D011480:Protease Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D016282:Aspartic Acid Endopeptidases; D002087:Butyrates; D010450:Endopeptidases; D006846:Hydrocarbons, Halogenated; D007093:Imidazoles; D010446:Peptide Fragments; D011480:Protease Inhibitors; D013449:Sulfonamides; C497115:4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid; C497114:4-chloro-N-(2,5-difluorophenyl)-N-((1R)-(4-fluoro-2-(3-(1H-imidazol-1-yl)propyl)phenyl)ethyl)benzenesulfonamide hydrochloride; D000096926:Benzenesulfonamides; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse