Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's disease (original) (raw)
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Therapeutic intervention for Alzheimer's disease with γ-secretase inhibitors: still a viable option?
Expert Opinion on Investigational Drugs, 2011
Introduction: Compounds that inhibit or modulate g-secretase, the pivotal enzyme which generates b-amyloid (Ab), are potential therapeutics for Alzheimer's disease (AD). Areas covered: This article briefly reviews the profile of g-secretase inhibitors that have reached the clinic and discusses the clinical issues surrounding this new class of anti-AD compounds. Expert opinion: g-Secretase inhibitors may cause significant toxicity in humans. Two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of detrimental cognitive and functional effects of the drug. These detrimental effects were mainly ascribed to the inhibition of Notch processing and the accumulation of the neurotoxic precursor of Ab resulting from the block of the g-secretase cleavage activity on amyloid precursor protein. New Notch-sparing g-secretase inhibitors are being developed with the hope of overcoming the previous setbacks. It has also been argued that g-secretase inhibitors should be used in the very early stages of the disease progression when neuronal loss is still limited. Thus, the inclusion of patients with mild-to-moderate AD in the semagacestat Phase III trials could also explain the negative outcome of these studies. Understanding the reasons for this failure may be important for future research on effective treatments for this devastating disease.
Current Topics in Medicinal Chemistry, 2011
According to the-amyloid (A) hypothesis, compounds that inhibit or modulate secretase, the pivotal enzyme that generates A , are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and nontransgenic animal models of AD have indicated that secretase inhibitors, administered by the oral route, are able to lower brain A concentrations. However, scanty data are available on the effects of these compounds on brain A deposition after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound acutely administered (DAPT).-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 secretase shifting its cleavage activity from longer to shorter-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 A brain pathology and learning depend on their activity on-secretase or on other biological targets. The most studied-secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the generation of A in the cerebrospinal fluid of healthy humans. Unfortuantely, 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 A (the carboxy-terminal fragment of APP, or CTF) resulting from the block of the-secretase cleavage activity on APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R-flurbiprofen), a putative-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notchsparing-secretase inhbitors and more potent, more brain penetrant-secretase modulators are being developed with the hope of overcoming the previous setbacks.
REVIEW: γ-Secretase Inhibitors for the Treatment of Alzheimer's Disease: The Current State
CNS Neuroscience & Therapeutics, 2010
Aims: Drugs currently used for the treatment of Alzheimer's disease (AD) partially stabilize patients' symptoms without modifying disease progression. Brain accumulation of oligomeric species of β-amyloid (Aβ) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being spent to identify drugs able to interfere with proteases regulating Aβ formation from amyloid precursor protein (APP). This article briefly reviews the profile of γ -secretase inhibitors, compounds that inhibit γ -secretase, the pivotal enzyme that generates Aβ, and that have reached the clinic. Discussion: Several classes of potent γ -secretase inhibitors have been designed and synthesized. Preclinical studies have indicated that these compounds are able to lower brain Aβ concentrations and, in some cases, reduce Aβ plaque deposition in transgenic mouse models of AD. The most developmentally advanced of these compounds is semagacestat, presently in Phase III clinical trials. In animals, semagacestat reduced Aβ levels in the plasma, cerebrospinal fluid (CSF), and the brain. However, studies have not reported on its cognitive effects. Studies in both healthy volunteers and patients with AD have demonstrated a dosedependent inhibition of plasma Aβ levels, and a recent study in healthy subjects demonstrated a robust, dose-dependent inhibition of newly generated Aβ in the CSF after single oral doses. Conclusions: Unfortunately, γ -secretase inhibitors may cause intestinal goblet cell hyperplasia, thymus atrophy, decrease in lymphocytes, and alterations in hair color, effects associated with the inhibition of the cleavage of Notch, a protein involved in cell development and differentiation. Nevertheless, at least other two promising γ -secretase inhibitors are being tested clinically. This class of drugs represents a major hope to slow the rate of decline of AD.
According to the -amyloid (A ) hypothesis, compounds that inhibit or modulate secretase, the pivotal enzyme that generates A , are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and nontransgenic animal models of AD have indicated that secretase inhibitors, administered by the oral route, are able to lower brain A concentrations. However, scanty data are available on the effects of these compounds on brain A deposition after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound acutely administered (DAPT). -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 secretase shifting its cleavage activity from longer to shorter -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 A brain pathology and learning depend on their activity on -secretase or on other biological targets. The most studied -secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the generation of A in the cerebrospinal fluid of healthy humans. Unfortuantely, 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 A (the carboxy-terminal fragment of APP, or CTF ) resulting from the block of the -secretase cleavage activity on APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R-flurbiprofen), a putative -secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notchsparing -secretase inhbitors and more potent, more brain penetrant -secretase modulators are being developed with the hope of overcoming the previous setbacks.
Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease
Alzheimer's research & therapy, 2010
Introduction: Inhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. Methods: In vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aβ40), and Notch εsite cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aβ production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aβ was determined in the PDAPP transgene model of AD, as well as in wildtype FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aβ reduction vs. Notch signaling endpoints in periphery. Results: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75-to 120-fold selectivity for inhibiting Aβ production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aβ in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aβ was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested.
Interacting with γSecretase for Treating Alzheimer's Disease: From Inhibition to Modulation
Current Medicinal Chemistry, 2011
Drugs currently used for the treatment of Alzheimer's disease (AD) produce limited clinical benefits, and there is no diseasemodifying therapy yet available. Compounds that inhibit or modulate-secretase, the pivotal enzyme that generates-amyloid (A), are potential therapeutics for AD. This article briefly reviews the profile of-secretase inhibitors and modulators that have reached the clinic. Studies in both transgenic and non-transgenic animal models of AD have indicated that secretase inhibitors, administered by the oral route, are able to lower brain A concentrations. However, scanty data are available on the effects of these compounds on brain A deposition after prolonged administration.-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen, skin, and decrease in lymphocytes and alterations in hair color in experimental animals and in man, effects believed to be associated with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effect of the drug. These detrimental effects were mainly ascribed to the inhibition of the processing of an unknown substrate of-secretase. It has been also hypothesized that the detrimental cognitive effects observed after semagacestat administration are due to the accumulation of the neurotoxic precursor of A (the carboxy-terminal fragment of amyloid precursor protein, APP, or CTF) resulting from the block of the-secretase cleavage activity on APP. Some non-steroidal anti-inflammatory drugs and other small organic molecules have been found to modulate secretase shifting its cleavage activity from longer to shorter A species without affecting Notch cleavage. However, two large Phase III studies in mild AD patients with tarenflurbil, a putativesecretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New more selective-secretase inhibitors and more potent, more brain penetrant-secretase modulators are being developed with the hope of overcoming the previous setbacks. Further understanding of the reasons of the failures of these-secretase-based drugs in AD may be important for the future research on effective treatments for this devastating disease.
Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain
Journal of Neurochemistry, 2009
Converging lines of evidence implicate the beta-amyloid peptide (Ab) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce Ab production by functionally inhibiting g-secretase, the activity responsible for the carboxy-terminal cleavage required for Ab production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon Ab production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-di¯uoro-phenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP V717F reduces brain levels of Ab in a dose-dependent manner within 3 h. These studies represent the ®rst demonstration of a reduction of brain Ab in vivo. Development of such novel functional g-secretase inhibitors will enable a clinical examination of the Ab hypothesis that Ab peptide drives the neuropathology observed in Alzheimer's disease.