Advances in the identification of β-secretase inhibitors

Hamada, Y.; Kiso, Yoshiaki

doi:10.1517/17460441.2013.784267

Cited by 29 publications

(18 citation statements)

References 108 publications

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“…This mutation was identified from a set of whole‐genome sequence data of 1795 Icelandic people as a gene with a low risk of AD and protects against AD and age‐related decline. This finding appears to verify the validity of the amyloid hypothesis in the AD pathology …”

Section: β‐Secretase Inhibitorssupporting

confidence: 78%

New directions for protease inhibitors directed drug discovery

Hamada

Kiso

2016

Biopolymers

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Proteases play crucial roles in various biological processes, and their activities are essential for all living organisms-from viruses to humans. Since their functions are closely associated with many pathogenic mechanisms, their inhibitors or activators are important molecular targets for developing treatments for various diseases. Here, we describe drugs/drug candidates that target proteases, such as malarial plasmepsins, β-secretase, virus proteases, and dipeptidyl peptidase-4. Previously, we reported inhibitors of aspartic proteases, such as renin, human immunodeficiency virus type 1 protease, human T-lymphotropic virus type I protease, plasmepsins, and β-secretase, as drug candidates for hypertension, adult T-cell leukaemia, human T-lymphotropic virus type I-associated myelopathy, malaria, and Alzheimer's disease. Our inhibitors are also described in this review article as examples of drugs that target proteases. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 563-579, 2016.

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Section: β‐Secretase Inhibitorssupporting

confidence: 78%

New directions for protease inhibitors directed drug discovery

Hamada

Kiso

2016

Biopolymers

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“…As BACE1 knockout transgenic mice demonstrated normal survival, this indicated a promising direction of study, in which BACE1 is a molecular target for the development of AD drugs [9]. At present, many BACE1 inhibitors have been revealed, including those in our study [10][11][12][13][14][15][16].…”

Section: Pathology Of Alzheimer's Diseasementioning

confidence: 53%

“…An early inhibitor of BACE1, an aspartic protease, was designed on the basis of a substrate transition-state concept, as well as that of other aspartic proteases, such as renin and HIV protease, which have a substrate transition-state analogue at the P 1 position [10][11][12][13][14][15][16]. It is wellknown that the Swedish mutant APP (K670N and M671L double mutation, Figure 1A) is cleaved faster than wild-type APP by BACE1, which results in increased Aβ 1-42 and Aβ 1-40 levels.…”

Section: Early Peptidic Bace1 Inhibitorsmentioning

confidence: 99%

Discovery of BACE1 Inhibitors for the Treatment of Alzheimer’s Disease

Hamada¹,

Kiso²

2017

Quantitative Structure-Activity Relationship

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Alzheimer's disease is the most common cause of dementia. According to the amyloid hypothesis, β-secretase (BACE1) is a promising molecular target for the development of anti-Alzheimer's disease drugs. BACE1 triggers the formation of the amyloid-β (Aβ) peptides that are the main component of senile plaques in the brain of patients with Alzheimer's disease. As BACE1 cleaves the amyloid precursor protein at the N-terminus of the Aβ domain, BACE1 inhibitors reduce the Aβ level in the brain. Previously, we designed a series of peptidic inhibitors that possessed a substrate transition-state analogue, and the structure-activity relationship of our inhibitors was evaluated, based on docking and scoring, using the docking simulation software Molecular Operating Environment (MOE). However, there was no association between the scoring values and the inhibitory activities at the P 2 position. Hence, we hypothesized that the interaction of the P 2 position of the inhibitor with the S 2 site of BACE1 was critical for the mechanism of inhibition, and we proposed the novel concept of 'electron donor bioisostere' for drug discovery. Using this concept, we designed potent small molecule non-peptidic BACE1 inhibitors.

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“…There are many interesting reviews on the pharmacology and medicinal chemistry of BACE inhibitors (in chronological order): 2012: [159], 2013: [160][161][162], 2014: [163,164].…”

Section: Drugs Interacting With Beta Secretasementioning

confidence: 99%

Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014

Froestl

Muhs

Pfeifer

2014

JAD

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Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review on Drugs interacting with Enzymes was accepted in August 2012. However, this field is very dynamic. New potential targets for the treatment of Alzheimer's disease were identified. This update describes drugs interacting with 60 enzymes versus 43 enzymes in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through April 2014.

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Advances in the identification of β-secretase inhibitors

Cited by 29 publications

References 108 publications

New directions for protease inhibitors directed drug discovery

New directions for protease inhibitors directed drug discovery

Discovery of BACE1 Inhibitors for the Treatment of Alzheimer’s Disease

Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014

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