Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's disease

INTRODUCTION: In an attempt of altering the natural history of Alzheimer's disease (AD), several compounds have been developed with the aim of inhibiting γ-secretase, the enzymatic complex generating β-amyloid (Aβ) peptides (Aβ(1 - 40) and Aβ(1 - 42)), from amyloid precursor protein (APP). APP is believed to be involved in the pathophysiological cascade of AD. AREAS COVERED: This article briefly reviews the profile of γ-secretase inhibitors that have reached the clinic. The paper reviews studies from the primary English literature on γ-secretase inhibitors published before November 2011, searching through the PubMed database of NCBI by author and the following keywords: drugs targeting β-amyloid, γ-secretase inhibitors, dementia syndromes and Alzheimer's disease. EXPERT OPINION: 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 prolonged administration. γ-Secretase inhibitors may cause significant toxicity in experimental animals and in humans 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 effects of the drug, possibly due to its lack of selectivity on APP processing. New APP-selective γ-secretase inhibitors are being developed with the hope of overcoming the previous setbacks.     

The CC genotype of transforming growth factor-β1 increases the risk of late-onset Alzheimer's disease and is associated with AD-related depression

Transforming growth factor-β1 (TGF-β1) is a neurotrophic factor that exerts neuroprotective effects against β-amyloid-induced neurodegeneration. Recently, a specific impairment of the TGF-β1 signaling pathway has been demonstrated in Alzheimer's disease (AD) brain. TGF-β1 is also involved in the pathogenesis of depressive disorders, which may occur in 30-40% of AD patients. The TGF-β1 gene contains single nucleotide polymorphisms (SNPs) at codon +10 (T/C) and +25 (G/C), which are known to influence the level of expression of TGF-β1. We investigated TGF-β1 +10 (T/C) and +25 (G/C) SNPs and allele frequencies in 131 sporadic AD patients and in 135 healthy age- and sex-matched controls. Genotypes of the TGF-β1 SNPs at codon +10 (T/C) and +25 (G/C) did not differ between AD patients and controls, whereas the allele frequencies of codon +10 polymorphism showed a significant difference (P = 0.0306). We also found a different distribution of the +10 (C/C) phenotype (continuity-corrected χ(2) test with one degree of freedom = 4.460, P = 0.0347) between late onset AD (LOAD) patients and controls (P = 0.0126), but not between early onset AD (EOAD) patients and controls. In addition, the presence of the C/C genotype increased the risk of LOAD regardless of the status of apolipoprotein E4 (odds ratio [OR] = 2.34; 95% CI = 1.19-4.59). Compared to patients bearing the T/T and C/T polymorphisms, LOAD TGF-β1 C/C carriers also showed > 5-fold risk to develop depressive symptoms independently of a history of depression (OR = 5.50; 95% CI = 1.33-22.69). An association was also found between the TGF-β1 C/C genotype and the severity of depressive symptoms (HAM-D(17) ≥ 14) (P < 0.05). These results suggest that the CC genotype of the TGF-β1 gene increases the risk to develop LOAD and is also associated with depressive symptoms in AD.     

γ-secretase inhibitors and modulators for the treatment of Alzheimer's disease: disappointments and hopes

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.     

Effect of fibronectin on expression of integrin α5β1 in trabecular meshwork cell in patients with primary open-angle glaucoma

目的 探讨纤维连接蛋白(FN)对体外培养的原发性开角型青光眼(POAG)患者小梁网细胞整合素α5β1表达及细胞存活的影响.方法 体外培养POAG患者小梁网细胞,分别加入不同浓度的FN(0、5、10、20、40、100μg/ml)培养.采用免疫细胞化学法观察各组细胞整合素α5β1的表达及细胞存活情况.结果 随着FN浓度增加,整合素α5β1表达增强.在FN低浓度(0-40 μg/ml)范围内,阳性细胞面积增多;而在FN 100μg/ml时阳性细胞面积减少.结论 FN影响小梁网细胞外基质,参与眼内压的调节.     

The economic impact of neuropsychiatric symptoms in Alzheimer's disease: can drugs ease the burden?

The majority of patients with Alzheimer's disease (AD) will have clinically significant neuropsychiatric symptoms during the course of their disease. There is growing evidence that neuropsychiatric symptoms increase direct costs of care in patients with AD, especially the costs associated with formal long-term care and unpaid caregiving. For example, we have estimated that a 1-point worsening of the neuropsychiatric inventory score is associated with an incremental increase of between USD 247 and USD 409 per year in total direct costs of care based upon year 2001 US dollars, depending on the value of unpaid caregiving. Although data are still limited, there have been a series of well designed, controlled clinical trials that have established the efficacy of several drugs used in the treatment of neuropsychiatric symptoms in patients with AD. The economic impact of using efficacious drugs to treat neuropsychiatric symptoms in patients with AD has not been evaluated formally. To successfully complete formal economic evaluations of these drugs there is a need for more research to refine methods for determining the economic value of unpaid caregiving and to collect more data concerning the incremental effects of neuropsychiatric symptoms on QOL, costs of care and survival. The current ongoing treatment trials that are collecting economic and QOL data as a part of the trial will be able to perform cost-effectiveness and cost-utility analyses of these new efficacious drugs. These economic evaluations will provide important information for decision makers who are formulating healthcare policy for the treatment of patients with AD.     

Selective enhancement of contractions to α1-adrenergic receptor activation in the aorta of mice with sickle cell disease

Sickle cell disease (SCD), the most common inherited hematologic disorder in the United States and the most common single gene disorder in the world, causes substantial morbidity and mortality. The major pathobiologic processes that underlie SCD include vaso-occlusion, inflammation, procoagulant processes, hemolysis, and altered vascular reactivity. The present study examined the vasoactive response to a-adrenergic activation in a murine model of SCD. Isolated aortas from sickle mice as compared with wild-type mice exhibit heightened contractions to norepinephrine and phenylephrine; such responses were completely blocked by an a1-receptor antagonist, prazosin. Aortas from either group exhibited comparable contractile responses to potassium chloride and the thromboxane agonist U46619 and no contractile response to an a2-adrenergic receptor agonist, UK14304. We conclude that there is an exaggerated vasoconstrictive response to a1-receptor agonists in SCD. Because sickle crisis is induced by diverse forms of stress, the latter attended by increased adrenergic activity, our findings may be relevant to the occurrence of sickle crisis. We also suggest that such heightened reactivity may contribute to vaso-occlusive processes that underlie ischemic injury in SCD. Finally, our findings urge caution in the use of phenylephrine in patients with SCD.     

GSK3β/β-catenin signaling is correlated with the differentiation of glioma cells induced by wogonin

Malignant gliomas are the most common and most aggressive primary brain tumor, and for which differentiation therapy has emerged as a promising candidate strategy. In this study, we used in vitro and in vivo assays to examine the differentiation effects of wogonin, a major active constituent of Scutellaria baicalensis, on glioma C6 and U251 cells. We found that wogonin can suppress cell proliferation and induce G0/G1 arrest under a concentration-dependent manner. Wogonin also triggered significant reduction in the G1 cell-cycle regulatory proteins cyclin D1, cyclin-dependent kinase 2 and 4 along with overexpression of cell-cycle inhibitory proteins p27. Immunofluorescence and western blot analysis indicated that wogonin increased the expression of lineage-specific differentiation marker glial fibrillary acidic protein (GFAP). In mechanisms, we verified that wogonin significantly diminished the phosphorylated level of protein kinase B (AKT), and maintenance of low β-catenin expression level was dependent on glycogen synthase kinase 3β (GSK3β) activation at Ser9. Blocking GSK3β/β-catenin pathway was required for wogonin-induced proliferation inhibition and terminal differentiation by using canonical activator lithium chloride (LiCl) and inhibitor dickkopf-1 (Dkk1). Moreover, intravenous administration of wogonin delayed the growth of C6 glioma in the intracranial tumor model. These findings provide the evidence and mechanistic support for wogonin-based differentiation therapies for malignant glioblastoma. Furthermore, inhibition of GSK3β/β-catenin pathway may be a key and requisite factor in glioma differentiation.     

Patents targeting γ-secretase inhibition and modulation for the treatment of Alzheimer's disease: 2004 – 2008

Background: Although Alzheimer's disease has been defined for over a century, at present there is no effective treatment. Amyloid deposition and plaque formation are widely believed to contribute to the pathology of the disease. As the etiology of plaque formation has become better understood, the search for therapies has bred small molecules capable of inhibiting or regulating the activity of γ-secretase. Objective: This paper reviews patents from the past 4 years claiming modulators or inhibitors of γ-secretase as a treatment for Alzheimer's disease. Method: One or two compounds from each patent were selected to represent the claimed chemical space. Compound selection was influenced by literature accounts, which are also discussed. Although an attempt has been made to include major contributions in the field, the list of patents reviewed should not be considered exhaustive. Conclusion: This review seeks to expand upon a previous review covering patents from 2000 – 2004. Since then there has been an increase in the number of structural and mechanistic approaches being pursued and several compounds have entered the clinic.     

Development of semagacestat (LY450139), a functional γ-secretase inhibitor,for the treatment of Alzheimer's disease

Background: Alzheimer's disease is thought to be caused by increased formations of neurotoxic amyloid beta (Aβ) peptides, which give rise to the hallmark amyloid plaques. Therefore, pharmacological agents that reduce Aβ formation may be of therapeutic benefit. Objective: This paper reviews the pharmacology and chemical efficacy of an Aβ-lowering agent, semagacestat (LY450139). Methods: A review of the published literature pertaining to semagacestat was obtained using several electronic search engines; unpublished data on file at Eli Lilly and Co. were used as supplementary material. Results/conclusions: Semagacestat treatment lowers plasma, cerebrospinal fluid and brain Aβ in a dose-dependent manner in animals and plasma and cerebrospinal fluid Aβ in humans, compared with placebo-treated patients. On the basis of extant data, semagacestat seems to be well tolerated, with most adverse events related to its actions on inhibition of peripheral Notch cleavage. Thus far, clinical efficacy has not been detectable because of the short duration of the current trials. Phase III trials with 21 months of active treatment are currently underway.     

Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer's disease: tangle formation, amyloid-β, and microglia in Alzheimer's disease

Pathological hallmarks of Alzheimer's disease (AD) include senile plaques, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaques are composed of amyloid-β (Aβ) and are surrounded by microglia, a primary immune effector cell in the central nervous system. NFTs are formed by the intraneuronal accumulation of hyperphosphorylated tau, and progressive synaptic and neuronal losses closely correlate with cognitive deficits in AD. Studies on responsible genes of familial AD and temporal patterns of pathological changes in brains of patients with Down's syndrome (Trisomy 21), who invariably develop neuropathology of AD, have suggested that Aβ accumulation is a primary event that influences other AD pathologies. Although details of the interaction between AD pathologies remain unclear, experimental evidences to discuss this issue have been accumulated. In this paper, we review and discuss recent findings that link the AD pathologies to each other. Further studies on the interaction between pathologies induced in AD brain may contribute to provide deep insight into the pathogenesis of AD and to develop novel therapeutic, prophylactic, and early diagnostic strategies for AD.     

The epidemic of Alzheimer's disease. How can we manage the costs?

Alzheimer's disease is one of several diseases of the elderly that has recently come into prominence for a number of reasons. First, its prevalence is set to increase as a result of the aging of Western populations. Secondly, the use of institutional care has fallen as a result of major policy changes in many countries, and this has caused a shift in the pattern of care for the elderly. Finally, the advent of innovative pharmacotherapy has caused third-party payers and clinicians to question the way in which this disease is best managed. International epidemiological data for Western populations point to a potentially considerable increase in the prevalence of the disease over the next 2 decades. Although the cost estimates of the disease vary widely among, or indeed, within different Western countries, they may be considerable. It is clear that innovative strategies, e.g. the use of respite care, sheltered housing and pharmacotherapy, might serve to limit the amount of time patients spend in institutional care. Even a small reduction in this form of care might be sufficient to offset the costs of treatment. What is lacking today are clear demonstrations as to how these new strategies might contribute to the overall management of this complex and multifactorial disease: this should be the joint focus of care providers and the pharmaceutical industry in the near future.     

Is memantine a breakthrough in the treatment of moderate-to-severe Alzheimer's disease?

Over stimulation of the NMDA receptor by glutamate has long been considered to have a role in Alzheimer's disease (AD). Memantine, a non-competitive antagonist of NMDA receptors, has recently been tested in moderate-to-severe AD. At 28 weeks, there was a small significant mean difference of 0.3 in favour of memantine, showing benefit in the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) global score. The other primary efficacy variable was the Alzheimer's disease Cooperative Study Activities of Daily Living Inventory, modified for more severe dementia (ADCS-ADL-sev) and there was significantly less deterioration in the ADCSADL-sev score in the memantine group than in the placebo group (2.1 versus 3.4, respectively). As there are no drugs commonly used for their effectiveness in moderate-to-severe AD, any drug that causes a benefit, however small, as memantine has been shown to do in this trial, represents a breakthrough.     

β-receptor antagonist treatment prevents activation of cell death signaling in the diabetic heart independent of its metabolic actions

We have previously shown that metoprolol improves function in the diabetic heart, associated with inhibition of fatty acid oxidation and a shift towards protein kinase B signaling. The aim of this study was to determine the relative importance of these metabolic and signaling effects to the prevention of cellular damage. Diabetes was induced in male Wistar rats by a single IV injection of 60mg/kg streptozotocin, and treated groups received 15mg/kg/day metoprolol delivered subcutaneously by osmotic pumps. Echocardiography was performed 6weeks after streptozotocin injection, and the hearts immediately excised for histological and biochemical measurements of lipotoxicity, apoptosis, signaling and caveolin/caspase interactions. Metoprolol improved stroke volume and cardiac output, associated with attenuation of TUNEL staining and a more modest attenuation of caspase-3; however, the positive TUNEL staining was not associated with an increase in apoptosis or cell regeneration markers. Metoprolol inhibited CPT-1 without affecting CD36 translocation, associated with increased accumulation of triglycerides and long chain acyl CoA in the cytoplasm, and no effect on oxidative stress. Metoprolol induced a shift from protein kinase A to protein kinase B-mediated signaling, associated with a shift in the phosphorylation patterns of BCl-2 and Bad which favored BCl-2 action. Metoprolol also increased the interaction of activated caspase-3 with caveolins 1 and 3 outside caveolae. The actions of metoprolol on fatty acid oxidation do not prevent lipotoxicity; its beneficial effect is more likely to be due to pro-survival signaling and sequestration of activated caspase-3 by caveolins.     

Chronic treatment with a novel γ-secretase modulator, JNJ-40418677, inhibits amyloid plaque formation in a mouse model of Alzheimer's disease

BACKGROUND AND PURPOSE

γ-Secretase modulators represent a promising therapeutic approach for Alzheimer''s disease (AD) because they selectively decrease amyloid β 42 (Aβ42), a particularly neurotoxic Aβ species that accumulates in plaques in the brains of patients with AD. In the present study, we describe the in vitro and in vivo pharmacological properties of a potent novel γ-secretase modulator, 2-(S)-(3,5-bis(4-(trifluoromethyl)phenyl)phenyl)-4-methylpentanoic acid (JNJ-40418677).

EXPERIMENTAL APPROACH

The potency and selectivity of JNJ-40418677 for Aβ reduction was investigated in human neuroblastoma cells, rat primary neurones and after treatment with single oral doses in non-transgenic mouse brains. To evaluate the effect of JNJ-40418677 on plaque formation, Tg2576 mice were treated from 6 until 13 months of age via the diet.

KEY RESULTS

JNJ-40418677 selectively reduced Aβ42 secretion in human neuroblastoma cells and rat primary neurones, but it did not inhibit Notch processing or formation of other amyloid precursor protein cleavage products. Oral treatment of non-transgenic mice with JNJ-40418677 resulted in an excellent brain penetration of the compound and a dose- and time-dependent decrease of brain Aβ42 levels. Chronic treatment of Tg2576 mice with JNJ-40418677 reduced brain Aβ levels, the area occupied by plaques and plaque number in a dose-dependent manner compared with transgenic vehicle-treated mice.

CONCLUSIONS AND IMPLICATIONS

JNJ-40418677 selectively decreased Aβ42 production, showed an excellent brain penetration after oral administration in mice and lowered brain Aβ burden in Tg2576 mice after chronic treatment. JNJ-40418677 therefore warrants further investigation as a potentially effective disease-modifying therapy for AD.     

The ERK1/2 pathway participates in the upregulation of the expression of mesenteric artery α1 receptors by intravenous tail injections of mmLDL in mice

Minimally modified low density lipoprotein (mmLDL) is a risk factor for cardiovascular diseases. However, no studies examining the effect of mmLDL on vascular smooth muscle receptors have been released. The current study investigated the effect of mmLDL on the mesenteric artery α₁ adrenoceptor and the molecular mechanisms. Mice were divided into the normal saline (NS), mmLDL, and mmLDL + U0126 groups. In the mmLDL + U0126 group, the animals were subjected to an intravenous tail injection of mmLDL and an intraperitoneal injection of U0126. Vascular tension caused by noradrenaline (NA) in mesenteric arteries was measured with a sensitive myograph system. The serum levels of oxLDL, TNF-α, and IL-1β were detected using enzyme-linked immunosorbent assays. The expressions of the α₁ adrenoceptor, the α₂ adrenoceptor, TNF-α, IL-1β, and pERK1/2 were detected using real-time polymerase chain reactions and Western blot analysis. Compared with the NS group, the mmLDL group exhibited a noticeably enhanced NA shrinkage dose–response curve and a significantly increased E_max value (P < 0.01). Prazosin (α₁ adrenoceptor antagonist) caused a noticeable right shift of the dose–response curve. U0126 inhibited the increases in the serum levels and vessel wall expression of IL-1β and TNF-α and enhanced the NA shrinkage dose–response curve caused by mmLDL, as observed by a significantly decreased E_max value (P < 0.01). It inhibited the increased α₁ adrenoceptor expression caused by mmLDL. The serum levels of IL-1β and TNF-α demonstrated a positive correlation with the NA-induced maximum shrinkage percentage. U0126 inhibited the mmLDL-induced increase in the pERK1/2 protein level in the vessel wall. In conclusion, mmLDL increased the serum levels of IL-1β and TNF-α in vivo by activating the ERK1/2 pathway, which resulted in α₁ receptor-mediated vasoconstriction and an increase in the expression of α₁ adrenoceptor. The results of this study may provide new ideas for the prevention and cure of cardiovascular diseases in the future.     

Elevation of BACE in an Aβ rat model of Alzheimer's disease: exacerbation by chronic stress and prevention by nicotine

In Alzheimer's disease (AD), progressive accumulation of β-amyloid (Aβ) peptides impairs nicotinic acetylcholine receptor (nAChR) function by a mechanism that may involve α7 and α4β2-nAChR subtypes. Additionally, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), the rate-limiting enzyme in the pathogenic Aβ production pathway, is expressed at high levels in hippocampal and cortical regions of AD brains. We measured hippocampal area CA1 protein levels of BACE and α7- and α4β2-nAChR subunits using an Aβ rat model of AD (14-d osmotic pump i.c.v. infusion of 300 pmol/d Aβ peptides) in the presence and absence of chronic stress and/or chronic nicotine treatment. There was a significant increase in the levels of BACE in Aβ-infused rats, which were markedly intensified by chronic (4-6 wk) stress, but were normalized in Aβ rats chronically treated with nicotine (1 mg/kg b.i.d.). The levels of the three subunits α7, α4 and β2 were significantly decreased in Aβ rats, but these were also normalized in Aβ rats chronically treated with nicotine. Chronic stress did not further aggravate the reduction of nAChRs in Aβ-infused rats. The increased BACE levels and decreased nAChR levels, which are established hallmarks of AD, provide additional support for the validity of the Aβ i.c.v.-infused rat as a model of AD.     

Impact of estrogen therapy on Alzheimer's disease: a fork in the road?

The results of recent clinical studies have challenged our previously held view that estrogen therapy promotes neurological health and prevents or ameliorates Alzheimer's disease. A major question emerging from these studies is: how can there be such disparity between the basic science and epidemiological data that show that estrogen can protect neurons against degenerative insults and reduce the risk of Alzheimer's disease and the recent data (from the Women's Health Initiative Memory Study [WHIMS] trial and the trial of estrogen treatment for Alzheimer's disease), which show that hormone replacement therapy (HRT) showed no benefit and even a potential deleterious effect? Which set of data is correct? The proposition put forth in this review is that both sets of data are correct and that two major factors determine the efficacy of estrogen or HRT. First is the time at which estrogen therapy is initiated. The data indicate that initiation of therapy early in menopause and when neurons are in a healthy state, reduces the risk of Alzheimer's disease; whereas, estrogen therapy initiated after the disease has developed or decades following menopause is without benefit. Second, estrogen therapy is not the same as HRT and the type of progestogen used determines the outcome of the therapeutic intervention. Insights into the mechanisms of action of estrogen and progestogen in the brain provide a framework for understanding the paradox of the benefit of estrogen in the prevention of Alzheimer's disease versus the lack of benefit in treatment trials and in trials when HRT is instituted many years after menopause. Based on estrogen-inducible mechanisms, which have been elucidated in healthy neuron model systems, it would be predicted that estrogen therapy could be highly effective in preventing neurodegenerative disease by promoting neuronal defence and memory mechanisms. The mechanisms of action of estrogen also predict that estrogen therapy would be an ineffective strategy for reversing the pathology of Alzheimer's disease. In summary, the time at which estrogen therapy is initiated, the neurological status of the brain at the time of estrogen therapy initiation and the type of progestogen used all contribute to the efficacy of estrogen in preventing neurodegenerative disease and to sustaining neurological health and function. An estrogen advantage hypothesis is put forth that provides a unifying mechanism of estrogen action with implications for both the benefits and risks of estrogen therapy.     

Novel γ-secretase modulators for the treatment of Alzheimer's disease: a review focusing on patents from 2010 to 2012

Introduction: γ-Secretase is the enzyme responsible for the final step of amyloid precursor protein proteolysis to generate Aβ peptides including Aβ42 which is believed to be a toxic species involved in Alzheimer's disease (AD) progression. γ-Secretase modulators (GSMs) have been shown to selectively lower Aβ42 production without affecting total Aβ levels or the formation of γ-secretase substrate intracellular domains such as APP intracellular domain and Notch intracellular domain. Therefore, GSMs have emerged as an important therapeutic strategy for the treatment of AD.

Areas covered: The literature covering novel GSMs will be reviewed focusing on patents from 2010 to 2012.

Expert opinion: During the last review period (2008 – 2010) considerable progress was made developing GSMs with improved potency for lowering Aβ42 levels, but most of the compounds resided in unfavorable central nervous system (CNS) drug space. In this review period (2010 – 2012), there is a higher percentage of potent GSM chemical matter that resides in favorable CNS drug space. It is anticipated that clinical candidates will emerge out of this cohort that will be able to test the GSM mechanism of action in the clinic.