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Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein γ-Secretase for the Treatment of Alzheimer's Disease
TLDR
Preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide γ-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch and a reversal of contextual fear-conditioning deficits that are correlated with Aβ load is reported. Expand
Acute γ-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease
Transgenic mice (Tg2576) overexpressing the Swedish mutation of the human amyloid precursor protein display biochemical, pathological, and behavioral markers consistent with many aspects ofExpand
Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease.
TLDR
Acute treatment with the gamma-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine-t-butylester (DAPT) is suggested to provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease. Expand
Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1.
TLDR
In vitro enzyme results were supported by a human whole blood assay where etodolac also demonstrated a 10-fold selectivity for inhibition of PGHS-2 mediated TxB2 production, which may be key to explaining the clinically observed gastrointestinal safety of etdolac versus other marketed NSAIDs. Expand
Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.
TLDR
Side chain modification afforded the potent Notch-1-sparing GSI begacestat, selected for development for the treatment of Alzheimer's disease, which had improved in vivo potency. Expand
Inhibition of platelet and neutrophil phospholipase A2 by hydroxyeicosatetraenoic acids (HETES). A novel pharmacological mechanism for regulating free fatty acid release.
TLDR
A novel pharmacological action of HETEs on PLA2 which may have potential ramifications in the regulation of arachidonic acid metabolism is suggested. Expand
Modulation by hydroxyeicosatetraenoic acids (HETEs) of arachidonic acid metabolism in mouse resident peritoneal macrophages.
The effects of 5-, 5-lactone, 12- and 15-hydroxyeicosatetraenoic acids (HETEs) on the synthesis of leukotriene C4 (LTC4), thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) by mouse residentExpand
Brain and plasma exposure profiling in early drug discovery using cassette administration and fast liquid chromatography-tandem mass spectrometry.
TLDR
A method using reverse phase liquid chromatography-tandem mass spectrometry and cassette administration for in vivo brain and plasma exposure profiling was developed to assist early CNS drug discovery programs and provided early brain penetration information in several CNS exploratory and discovery programs. Expand
5-lipoxygenase: properties, pharmacology, and the quinolinyl(bridged)aryl class of inhibitors.
In conclusion, an effective modulator of the AA cascade for the treatment of asthma and other inflammatory diseases may require 5-LO inhibitory activity as well as LTD4 antagonism in order to limitExpand
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