Novel γ-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates

Takahashi, Yasuko; Fuwa, Haruhiko; Kaneko, Akane; Sasaki, Makoto; Yokoshima, Satoshi; Koizumi, Hifumi; Takebe, Tohru; Kobayashi, Toshiyuki; Iwatsubo, Takeshi; Tomita, Taisuke; Natsugari, Hideaki; Fukuyama, Tohru

doi:10.1016/j.bmcl.2006.04.025

Cited by 19 publications

(10 citation statements)

References 24 publications

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“…Cyclohexenone and two aryl groups arranged on a core six-membered ring, an intermediate in synthesis of natural products displayed significant inhibitory effects on γ-secretase (Takahashi et al, 2006).…”

Section: γ-Secretase Inhibitorsmentioning

confidence: 99%

Potential therapeutic agents against Alzheimer’s disease from natural sources

Park

2010

Arch. Pharm. Res.

106

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The average human life span in developed countries has increased to more than 80 years following rapid breakthrough and developments in modern medicine and science, resulting in prolonged life expectancy and increase in the population counts of the geriatric age group. This translates into a dramatic increase in disease burden of elderly patients suffering from senile disorders including neurodegenerative diseases, particularly Alzheimer's disease (AD). AD is characterized by the death of nerve cells in the cerebral cortex and is the most common subtype of dementia that affected 25 million people worldwide in 2000 and is expected to increase to 114 million by 2050. Despite the exponential growth in the number of AD patients, only acetylcholinesterase (AChE) inhibitors are being currently used to treat AD. It is well known that AChE inhibitors can alleviate the symptoms of AD but not halt the disease progression. Consequently, therapeutic agents against AD acting at various pathologic levels are needed. In the recent decade, natural products with anti-AD properties have attracted much attention. But very few natural products have been investigated in a scientifically justifiable method for these biological activities. Following a detailed research process, it is certain that natural products have a strong potential to develop biologically active compounds with new chemical structures. Many studies have been carried out to identify the naturally occurring anti-AD agents. This review article describes the molecular targets aiming at developing the anti-AD agents including the inhibition of AChE, inhibition of Aβ production by enhancing α-secretase (non-amyloidogenic pathway) or inhibiting β- and γ-secretases (amyloidogenic pathway), alleviating Aβ-induced neurotoxicity or reducing Aβ-induced neuroinflammation. In addition, this paper summarizes the potential of some of the natural products that might inhibit specific molecular targets and slow the progression of this disease.

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Section: γ-Secretase Inhibitorsmentioning

confidence: 99%

Potential therapeutic agents against Alzheimer’s disease from natural sources

Park

2010

Arch. Pharm. Res.

106

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“…29). The two six-membered ring enones (99) and (100) bear two aromatic-containing sidechains, and demonstrated low micromolar activity in an assay measuring -secretase dependent processing of an APP C-terminal fragment [121]. Binding studies with these classes of -secretase inhibitors have not been reported, and whether they interact with known sites on -secretase is as yet unknown, yet they provide further evidence of the considerable diversity tolerated by this unique enzymatic complex.…”

Section: Other -Secretase Inhibitorsmentioning

confidence: 96%

Recent Progress in the Medicinal Chemistry of γ-Secretase Inhibitors

Olson¹,

Albright²

2008

CTMC

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Abeta is implicated in the initiation and progression of Alzheimer's disease (AD) by the phenotypic analysis of mutations in three human genes that lead to inherited, early forms of AD and data from preclinical studies. Based on this evidence, gamma-secretase inhibitors are being actively pursued as potential AD therapeutics to reduce Abeta formation. This manuscript reviews recent progress in the medicinal chemistry of three major classes of gamma-secretase inhibitors: peptide isosteres, azepines, and sulfonamides. Peptide isosteres have been useful for demonstrating that presenilin is the catalytic subunit of gamma-secretase and probing the active site. The peptidic nature of these inhibitors has, however, interfered with their utility for in vivo studies. Instead, the pharmaceutical industry has focused on optimizing azepines and sulfonamides. Both azepines and sulfonamides bind to a common, allosteric site on presenilin that differs from the active site identified by the peptide isosteres. Significant progress in the optimization of both azepines and sulfonamides has led to compounds that inhibit brain Abeta synthesis in preclinical models and has culminated in the identification of gamma-secretase inhibitors, including LY-450139 and MK-0752, for human trials.

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“…Although one still sees the word design in terms of g-secretase inhibitors and modulators, its use is somewhat of a misnomer as the development of inhibitors has been based more on serendipity [Takahashi et al, 2006] than target-based rationale. Indeed the inhibitory or modulatory actions of compounds such as the NSAIDs (Fig.…”

Section: C-secretasementioning

confidence: 98%

Structure and modeling in the design of β‐ and γ‐secretase inhibitors

Holloway

Hunt

McGaughey

2009

Drug Development Research

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This review discusses the involvement of structure and modeling in the design of b-secretase (BACE-1) and g-secretase inhibitors as putative Alzheimer's Disease therapeutics. The early and broad availability of structural information for BACE-1, a membrane-tethered aspartyl protease, has led to the use of in silico methods in the overall design and optimization process. However, for g-secretase, an integral membrane protein, the lack of a detailed 3D structure has limited the application of computational methods. Drug Dev Res 70 : 70-93, 2009.

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Novel γ-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates

Cited by 19 publications

References 24 publications

Potential therapeutic agents against Alzheimer’s disease from natural sources

Potential therapeutic agents against Alzheimer’s disease from natural sources

Recent Progress in the Medicinal Chemistry of γ-Secretase Inhibitors

Structure and modeling in the design of β‐ and γ‐secretase inhibitors

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Novel γ-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates

Cited by 19 publications

References 24 publications

Potential therapeutic agents against Alzheimer’s disease from natural sources

Potential therapeutic agents against Alzheimer’s disease from natural sources

Recent Progress in the Medicinal Chemistry of &#947;-Secretase Inhibitors

Structure and modeling in the design of β‐ and γ‐secretase inhibitors

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Product

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Recent Progress in the Medicinal Chemistry of γ-Secretase Inhibitors