O3-06-07 Multi-compartmental pharmacodynamic assessment of the functional gamma-secretase inhibitor LY450139 in PDAPP transgenic mice and non-transgenic mice

May, Patrick C.; Yang, Zhihui; Li, Weiying; Hyslop, Paul A.; Siemers, Eric; Boggs, Leonard N.

doi:10.1016/s0197-4580(04)80220-3

Cited by 35 publications

(26 citation statements)

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“…As noted previously, however, the functional γ-secretase inhibitor LY450139 lowered Aβ species in brain, CSF, and plasma of mice and dogs as measured by ELISA [18][19][20]. Similarly, LY450139 administration to volunteers [22] or AD patients [23] dose-dependently lowers plasma Aβ.…”

Section: Use Of Biomarkers In Ad Drug Developmentsupporting

confidence: 55%

“…Preclinically, this molecule has been shown to lower Aβ in the brain, cerebrospinal fluid (CSF), and plasma of both mice and dogs [18][19][20]. Further, in a study of a transgenic mouse model of AD, after 5 months of treatment with LY450139 once per day, mice given 30 mg/kg showed less accumulation of Aβ in cortex and hippocampus than mice given vehicle [21].…”

Section: Introductionmentioning

confidence: 99%

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New pathways in drug discovery for alzheimer’s disease

Siemers

Dean²,

DeMattos³

et al. 2006

Curr Neurol Neurosci Rep

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Specific treatments for Alzheimer's disease (AD) were first introduced in the 1990s using the acetyl-cholinesterase inhibitors. More recently, the N-methyl-D-aspartate (NMDA) antagonist memantine has become available. Although these treatments do provide a modest improvement in the cognitive abnormalities present in AD, their pharmacology is based on manipulation of neurotransmitter systems, and there is no compelling evidence that they interfere with the underlying pathogenic process. Pathologic and genetic data have led to the hypothesis that a peptide called amyloid ss(Abeta) plays a primary role in the pathophysiology of AD. Several investigational therapies targeting Abeta are now undergoing clinical trials. This paper reviews the available data regarding Abeta-directed therapies that are in the clinic and summarizes the approach to biomarkers and clinical trial designs that can provide evidence of modification of the underlying disease process.

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Section: Use Of Biomarkers In Ad Drug Developmentsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

New pathways in drug discovery for alzheimer’s disease

Siemers

Dean²,

DeMattos³

et al. 2006

Curr Neurol Neurosci Rep

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“…1B and Table 1). Several benchmark GSIs including DAPT (Dovey et al, 2001), LY411575 (May et al, 2002), LY450139 (May et al, 2004), L685458 (Shearman et al, 2000) and DuPont E (Seiffert et al, 2000) were evaluated to compare potency and are summarized in Table 1.…”

Section: Downloaded Frommentioning

confidence: 99%

Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein γ-Secretase for the Treatment of Alzheimer's Disease

Martone

Zhou²,

Atchison³

et al. 2009

J Pharmacol Exp Ther

149

124

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The presenilin containing ␥-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. ␥-Secretase catalyzes the final step in the generation of A␤ 40 and A␤ 42 peptides from APP. Amyloid ␤-peptides (A␤ peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic A␤ peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide ␥-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits A␤ production with low nanomolar potency in cellular and cell-free assays of ␥-secretase function, and displaces a tritiated analog of GSI-953 from enriched ␥-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid A␤ levels, and a reversal of contextual fear-conditioning deficits that are correlated with A␤ load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dosedependent changes in plasma A␤ levels, confirming pharmacodynamic activity of GSI-953 in humans.This research was supported by Wyeth Research. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

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“…Semagacestat reduces the rate of formation of A␤ in whole cell assays, as well as in transgenic and nontransgenic mice, beagle dogs, and guinea pigs Hyslop et al, 2004;May et al, 2004;Lanz et al, 2006). A transgenic mouse model of AD was generated using a platelet-derived growth factor ␤ promoter driving a human APP minigene encoding the APP V171F mutation (PDAPP mouse).…”

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confidence: 99%

Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

Yi¹,

Hadden²,

Kulanthaivel³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Semagacestat is a functional ␥-secretase inhibitor that has been shown to reduce the rate of formation of amyloid-␤ in vitro and in vivo. This study was conducted to characterize the disposition of semagacestat in humans. After a single 140-mg dose of [ 14 C]semagacestat administered as an oral solution to six healthy male subjects, semagacestat was rapidly absorbed (T max ϳ0.5 h) and eliminated from the systemic circulation (terminal t 1/2 ϳ2.4 h). The major circulating metabolites of semagacestat, M2 (hydrolysis of the amide bond proximal to the benzazepine ring) and M3 (benzylic hydroxylation of the benzazepine ring), accounted for approximately 27 and 10% of total radioactivity exposure, respectively, as calculated from relative area under the plasma concentration versus time curve from 0 to 24 h derived from the plasma radiochro- Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by cognitive impairment. The prevalence rate is approximately 6% among those aged more than 65 years. Currently more than 4 million Americans suffer from AD, and this number is expected to quadruple by year 2050 as average lifespan increases (Rice et al., 2001;Joyce et al., 2007). AD has a substantial impact on patients, caregivers, and the healthcare system. Average total medical costs for AD patients are more than 5-fold higher than those for control populations. Development of pharmaceuticals for the treatment of AD would greatly benefit AD patients and society. The cause of AD is not yet clear. Pathological studies revealed the existence of neuritic plaques in the brains of AD patients (Desai and Grossberg, 2005;Blennow et al., 2006). The plaques are mainly composed of amyloid-␤ (A␤) peptides that are formed by the sequential cleavage of the amyloid precursor protein (APP). APP is first cleaved by the ␤-site APP-cleaving enzyme to form the N terminus of A␤, which is further cleaved by ␥-secretase at multiple sites to form A␤ isoforms ranging from 37 (A␤37) to 43 (A␤43) residues (Olson and Albright, 2008). Mutations in APP near cleavage sites resulting in the A␤ formation have been linked to AD in several families (Selkoe, 2001;Imbimbo, 2008). This observation suggests that a reduction in A␤ synthesis could slow the disease progression in patients with AD.Semagacestat, an azepine class ␥-secretase inhibitor, is one of a very few ␥-secretase inhibitors that have been advanced into clinical trials as potential disease-modifying agents for the treatment of AD (Olson and Albright, 2008). Semagacestat reduces the rate of formation of A␤ in whole cell assays, as well as in transgenic and nontransgenic mice, beagle dogs, and guinea pigs Hyslop et al., 2004;May et al., 2004;Lanz et al., 2006). A transgenic mouse model of AD was generated using a platelet-derived growth factor ␤ promoter driving a human APP minigene encoding the APP V171F mutation (PDAPP mouse). These mice express high levels of human mutant APP and progressively develop many of the pathologArticle, publication date, and citation ...

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O3-06-07 Multi-compartmental pharmacodynamic assessment of the functional gamma-secretase inhibitor LY450139 in PDAPP transgenic mice and non-transgenic mice

Cited by 35 publications

References 0 publications

New pathways in drug discovery for alzheimer’s disease

New pathways in drug discovery for alzheimer’s disease

Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein γ-Secretase for the Treatment of Alzheimer's Disease

Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

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