کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9002322 | 1118583 | 2005 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Reductions in β-amyloid concentrations in vivo by the γ-secretase inhibitors BMS-289948 and BMS-299897
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کلمات کلیدی
AβAPPDAPTβ-Amyloid - β-آمیلوئیدenzyme-linked immunosorbant assay - آنزیم ایمونوسیوربنت تست شدهAlzheimer's disease - بیماری آلزایمرELISA - تست الیزاSecretase - دبیرستانCerebrospinal fluid - مایع مغزی نخاعیCSF - مایع مغزی نخاعیγ-secretase inhibitor - مهارکننده γ-اسیدProteolytic processing - پردازش پروتئولیتیکamyloid precursor protein - پروتئین پیش ماده آمیلوئی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
A primary pathological feature of Alzheimer's disease is β-amyloid (Aβ)-containing plaques in brain and cerebral vasculature. Reductions in the formation of Aβ peptides by γ-secretase inhibitors may be a viable therapy for reducing Aβ in Alzheimer's disease. Here we report on the effects of two orally active γ-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 Aβ1-40 in APP-YAC mice with ED50 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 γ-secretase. BMS-289948 and BMS-299897 (100 mg/kg po) reduced brain and plasma Aβ1-40 rapidly (within 20 min) and maximally within 3 h. BMS-299897 also dose-dependently reduced cortical, cerebrospinal fluid (CSF), and plasma Aβ in guinea pigs with ED50 values of 30 mg/kg intraperitoneally, without affecting CSF levels of α-sAPP. The reductions in cortical Aβ correlated significantly with the reductions in both plasma (r2 = 0.77) and CSF (r2 = 0.61) Aβ. The decreases in Aβ were apparent at 3 and 6 h post-administration of BMS-299897, but not at 12 h. These results demonstrate that BMS-289948 and BMS-299897 are orally bioavailable, functional γ-secretase inhibitors with the ability to markedly reduce Aβ peptide concentrations in APP-YAC transgenic mice and in guinea pigs. These compounds may be useful pharmacologically for examining the effects of reductions in β-amyloid peptides in both animal models and in Alzheimer's disease.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 69, Issue 4, 15 February 2005, Pages 689-698
Journal: Biochemical Pharmacology - Volume 69, Issue 4, 15 February 2005, Pages 689-698
نویسندگان
Jeffery J. Anderson, Greg Holtz, Patricia P. Baskin, Mary Turner, Blake Rowe, Bowei Wang, Maria Z. Kounnas, Bruce T. Lamb, Donna Barten, Kevin Felsenstein, Ian McDonald, Kumar Srinivasan, Ben Munoz, Steven L. Wagner,