P4‐022: The Gamma Secretase Modulator EVP‐0015962 Improves Cognitive Deficits in Tg2576 Mice Concomitant With Decreases In Aβ<sub>42</sub>

Rogers, Kathryn; Leventhal, Liza; Hopp, Sarah C.; Miller, M E; Yang, Zhiyong; Hrdlicka, Lori; Lee, Winnie; Hodgdon, Hilliary; Nolan, Scott; Wen, Melody; Koperniak, Thomas; Spaulding, Darcie; Catana, Florentina; Chesworth, Richard; Shapiro, Gideon; Costa, Donald; Ahlijanian, Michael K.; Koenig, Gerhard; Felsenstein, Kevin M.

doi:10.1016/j.jalz.2010.08.082

Cited by 5 publications

(6 citation statements)

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“…Similar effects on A levels were observed in wild-type C57/BL6 mice and Sprague-Dawley rats following single oral administration of the agent [66]]. Chronic administration of EVP-15962 as a diet supplement (equivalent to 20 or 60 mg/kg/ day) to Tg2576 mice was associated to a significant decrease in the brain concentrations of A 1-42 levels and to a reduction of A aggregates [67]. Behavioral tests of cognitive ability were performed using the contextual fear conditioning and the Morris water maze paradigms.…”

Section: Evp-15962supporting

confidence: 60%

“…On the other hand, chronic treatment with EVP-15962 ( 12 months) of young Tg2576 mice (4-6 months) up to the age of 16-18 months did not show significant improvements of contextual memory at both doses. In the Morris water maze test, a partial recovery/blockade of the cognitive deficit of Tg2576 animals was seen following treatment with the 60 mg/kg/day dose [67]. Intitial clinical testing of EVP-15962 is expected to start in 2011.…”

Section: Evp-15962mentioning

confidence: 99%

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γ-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes

Imbimbo

Giardina²

2011

CTMC

177

141

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According to the β-amyloid (Aβ) hypothesis, compounds that inhibit or modulate γ secretase, the pivotal enzyme that generates Aβ, are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound acutely administered (DAPT). γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen and skin in experimental animals and in man. These toxic effects are likely due to inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Some non-steroidal anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate γ secretase shifting its cleavage activity from longer to shorter β-amyloid species without affecting Notch cleavage. Long-term histopathological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the observed in vivo effects on Aβ brain pathology and learning depend on their activity on γ-secretase or on other biological targets. The most studied γ-secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the generation of Aβ in the cerebrospinal fluid of healthy humans. Unfortunately, two large Phase 3 clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared to those receiving placebo. These detrimental effects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of Aβ (the carboxy-terminal fragment of APP, or CTFβ) resulting from the block of the γ-secretase cleavage activity on APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R flurbiprofen), a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notch-sparing γ-secretase inhibitors and more potent, more brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks.

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Section: Evp-15962supporting

confidence: 60%

Section: Evp-15962mentioning

confidence: 99%

γ-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes

Imbimbo

Giardina²

2011

CTMC

177

141

View full text Add to dashboard Cite

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“…As an extension to this series, tetrasubstituted phenyl compounds have been claimed in patent applications, with some typical examples shown in Figure . Although the structure remains undisclosed, data have been presented on EnVivo’s preclinical candidate EVP-0015962 ( 62 , structure not disclosed). , The in vitro Aβ 42 lowering activity of this compound was reported as an IC 50 of 0.12 μM in a human cellular assay and 0.489 μM in a neuronal cellular assay, without any effect on Notch-processing. Oral dosing of 10 and 30 mg/kg in rats led to a reduction in Aβ 42 brain levels of 22% and 38%, respectively, with brain levels of 2.8 and 8.3 μM.…”

Section: Nsaid Derived Gsmsmentioning

confidence: 99%

“…Chronic treatment of transgenic Tg2576 mice with a 20 or 60 (mg/kg)/day dosing over a 6-month period led to a lowering of brain plaque load of >81% at 20 mg/kg and >95% at 60 mg/kg. 62 was also tested in the contextual fear conditioning model after 30−33 weeks of treatment of Tg2576 mice at 20 or 60 (mg/kg)/day dosing or in the Morris water maze model after 47 weeks of treatment at 20 (mg/kg)/day . In these experiments, cognitive deficits in contextual and spatial working memory, respectively, could be reversed.…”

Section: Nsaid Derived Gsmsmentioning

confidence: 99%

γ-Secretase Modulators as Potential Disease Modifying Anti-Alzheimer’s Drugs

2010

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“…Brain exposures at 2.8 μM and 8.3 μM (5-and 17-fold of IC50) led to a 22% and 38% reduction in brain Aβ42 respectively. Chronic dosing at 20 and 60 mg/kg/day in APP transgenic mice for 6 months led to a lowering of brain plaque load of 81% and 95% respectively [126,127].…”

Section: γ-Secretase Modulators: a Loss Of Pharmacology?mentioning

confidence: 99%

γ-Secretase and its modulators: Twenty years and beyond

Xia

2019

Neuroscience Letters

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Twenty years ago, Wolfe, Xia, and Selkoe identified two aspartate residues in Alzheimer's presenilin protein that constitute the active site of the γ-secretase complex. Mutations in the genes encoding amyloid precursor protein (APP) or presenilin (PS) cause early onset familial Alzheimer's disease (AD), and sequential cleavages of the APP by β-secretase and γ-secretase/ presenilin generate amyloid β protein (Aβ), the major component of pathological hallmark, neuritic plaques, in brains of AD patients. Therapeutic strategies centered on targeting γ-secretase/ presenilin to reduce amyloid were implemented and led to several high profile clinical trials. This review article focuses on the studies of γ-secretase and its inhibitors/modulators since the discovery of presenilin as the γ-secretase. While a lack of complete understanding of presenilin biology renders failure of clinical trials, the lessons learned from some γ-secretase modulators, while premature for human testing, provide new directions to develop potential therapeutics. Imbalanced Aβ homeostasis is an upstream event of neurodegenerative processes. Exploration of γ-secretase modulators for their roles in these processes is highly significant, e.g., decreasing neuroinflammation and levels of phosphorylated tau, the component of the other AD pathological hallmark, neurofibrillary tangles. Agents with excellent human pharmacology hold great promise in suppressing neurodegeneration in pre-symptomatic or early stage AD patients.

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P4‐022: The Gamma Secretase Modulator EVP‐0015962 Improves Cognitive Deficits in Tg2576 Mice Concomitant With Decreases In Aβ₄₂

Cited by 5 publications

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γ-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes

γ-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes

γ-Secretase Modulators as Potential Disease Modifying Anti-Alzheimer’s Drugs

γ-Secretase and its modulators: Twenty years and beyond

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P4‐022: The Gamma Secretase Modulator EVP‐0015962 Improves Cognitive Deficits in Tg2576 Mice Concomitant With Decreases In Aβ42

Cited by 5 publications

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&#947;-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes

&#947;-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes

γ-Secretase Modulators as Potential Disease Modifying Anti-Alzheimer’s Drugs

γ-Secretase and its modulators: Twenty years and beyond

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P4‐022: The Gamma Secretase Modulator EVP‐0015962 Improves Cognitive Deficits in Tg2576 Mice Concomitant With Decreases In Aβ₄₂

γ-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes

γ-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes