P4-339 Stereoselective inhibition of amyloid beta peptide secretion by LY450139, a novel functional gamma secretase inhibitor

Gitter, Bruce D.; Czilli, Dan L.; Li, Weiying; Dieckman, Donna K.; Bender, Mark H.; Nissen, Jeffrey S.; Mabry, Thomas E.; Yin, Tinggui; Boggs, Leonard N.; McClure, Don B.; Little, Sheila P.; Johnstone, Edward D.; Audia, James E.; May, Patrick C.; Hyslop, Paul A.

doi:10.1016/s0197-4580(04)81897-9

Cited by 25 publications

(15 citation statements)

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“…(3) is a -secretase inhibitor developed at Eli-Lilly. LY-450139 is only 3-fold selective in inhibiting APP and Notch cleavage (APP IC 50 = 15 nM, Notch EC 50 = 49 nM) [14]. LY-450139 is the best documented -secretase inhibitor that has reached clinical testing and for which clinical studies have been fully published.…”

Section: Ly-450139 (Semagacestat)mentioning

confidence: 99%

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: Ly-450139 (Semagacestat)mentioning

confidence: 99%

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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“…2005). The γ‐secretase inhibitor, LY450139, a highly potent low molecular weight compound, significantly reduced Aβ levels in cell cultures permanently over‐expressing APP and in both wildtype and transgenic APP‐expressing mice (Gitter et al. , 2004; May et al.…”

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confidence: 99%

Differential effects of γ‐secretase and BACE1 inhibition on brain Aβ levels in vitro and in vivo

Elvang¹,

Volbracht²,

Pedersen³

et al. 2009

Journal of Neurochemistry

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Alzheimer’s disease (AD) is hypothesized to result from elevated brain levels of β‐amyloid peptide (Aβ) which is the main component of plaques found in AD brains and which cause memory impairment in mice. Therefore, there has been a major focus on the development of inhibitors of the Aβ producing enzymes γ‐secretase and β‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1). In this study, we investigated the Aβ‐lowering effects of the BACE1 inhibitor LY2434074 in vitro and in vivo, comparing it to the well characterized γ‐secretase inhibitor LY450139. We sampled interstitial fluid Aβ from awake APPswe/PS1dE9 AD mice by in vivo Aβ microdialysis. In addition, we measured levels of endogenous brain Aβ extracted from wildtype C57BL/6 mice. In our in vitro assays both compounds showed similar Aβ‐lowering effects. However, while systemic administration of LY450139 resulted in transient reduction of Aβ in both in vivo models, we were unable to show any Aβ‐lowering effect by systemic administration of the BACE1 inhibitor LY2434074 despite brain exposure exceeding the in vitro IC50 value several fold. In contrast, significant reduction of 40–50% of interstitial fluid Aβ and wildtype cortical Aβ was observed when infusing LY2434074 directly into the brain by means of reverse microdialysis or by dosing the BACE1 inhibitor to p‐glycoprotein (p‐gp) mutant mice. The effects seen in p‐gp mutant mice and subsequent data from our cell‐based p‐gp transport assay suggested that LY2434074 is a p‐gp substrate. This may partly explain why BACE1 inhibition by LY2434074 has lower in vivo efficacy, with respect to decreased Aβ40 levels, compared with γ‐secretase inhibition by LY450139.

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“…18,19 In a study of PDAPP mice treated with LY450139, accumulation of Ab in the brain was slowed during 5 months of treatment. 20 In a previous study in our laboratories, single doses of LY450139 were given to healthy subjects using doses of 1 to 50 mg, and changes in plasma Ab along with safety assessments and pharmacokinetic determinations were made (Eli Lilly and Company, data on file).…”

mentioning

confidence: 99%

Safety, Tolerability, and Changes in Amyloid β Concentrations After Administration of a γ-Secretase Inhibitor in Volunteers

Siemers

Skinner

Dean

et al. 2005

Clinical Neuropharmacology

213

151

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Amyloid beta (Abeta) may play a central role in the pathogenesis of Alzheimer disease. A functional gamma-secretase inhibitor, LY450139, was developed that inhibits Abeta formation in whole cell assays, transgenic mice, and beagle dogs. The authors wished to determine the safety and tolerability of this drug, and the reduction of Abeta in plasma and cerebrospinal fluid (CSF) after multiple doses. Volunteer subjects (N = 37) were studied using doses from 5 to 50 mg/day given for 14 days. Plasma and CSF concentrations of LY450139, Abeta(1-40) and Abeta(1-X) ("Abeta(total)") were determined, and safety and tolerability were assessed. The plasma half-life of LY450139 was approximately 2.5 hours. Pharmacokinetic analyses showed a linear relationship between dose and plasma concentrations, with a Cmax of 828 +/- 19.2 ng/mL after a 50-mg dose. Plasma Abeta concentrations decreased in a dose-dependent manner over a 6-hour interval following drug administration, with a maximum decrease of approximately 40% relative to baseline. After returning to baseline, Abeta concentrations were transiently increased. CSF Abeta concentrations were unchanged. Adverse events reported by subjects taking 5-mg, 20-mg, or 40-mg doses were similar to those reported by subjects taking placebo. Two of 7 subjects taking 50 mg/day experienced adverse events that may have been drug related. In this phase 1 volunteer study, reported adverse events after taking LY450139 were manageable. A dose-dependent reduction in plasma Abeta was demonstrated, and changes in plasma Abeta concentrations were temporally related to the pharmacokinetic characteristics of LY450139.

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P4-339 Stereoselective inhibition of amyloid beta peptide secretion by LY450139, a novel functional gamma secretase inhibitor

Cited by 25 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

Differential effects of γ‐secretase and BACE1 inhibition on brain Aβ levels in vitro and in vivo

Safety, Tolerability, and Changes in Amyloid β Concentrations After Administration of a γ-Secretase Inhibitor in Volunteers

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P4-339 Stereoselective inhibition of amyloid beta peptide secretion by LY450139, a novel functional gamma secretase inhibitor

Cited by 25 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

Differential effects of γ‐secretase and BACE1 inhibition on brain Aβ levels in vitro and in vivo

Safety, Tolerability, and Changes in Amyloid β Concentrations After Administration of a γ-Secretase Inhibitor in Volunteers

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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