Novel BACE1 inhibitors with a non-acidic heterocycle at the P1′ position

Suzuki, Kenji; Hamada, Y.; Nguyen, Jeffrey‐Tri; Kiso, Yoshiaki

doi:10.1016/j.bmc.2013.08.016

Cited by 13 publications

(5 citation statements)

References 38 publications

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“…The methyl ester of (2 S ,3 S )-allophenylnorstatin, itself a LTA 4 hydrolase inhibitor, 19 has been used as a building block for the preparation of BACE1 inhibitors, 20 photobiological switches, 21 and symmetrical peptidomimetic scaffolds; 22 it has also served as an intermediate for the preparation of a variety of other biologically active compounds, 23 as has the corresponding ethyl ester. 24 These two ester derivatives were prepared readily as follows (Scheme 4).…”

Section: Resultsmentioning

confidence: 99%

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A case study of the MAC (masked acyl cyanide) oxyhomologation of N,N-dibenzyl-l-phenylalaninal with anti diastereoselectivity: preparation of (2S,3S)-allophenylnorstatin esters

Buchotte

Guillot

et al. 2022

Org. Biomol. Chem.

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Section: Resultsmentioning

confidence: 99%

“…(2S,3S)-3-Amino-2-hydroxy-4-phenylbutanoic acid, (−)-allophenylnorstatin (20). Palladium (10 wt%) on activated carbon (6 mg) was added to a solution of benzyl (2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutanoate 19 (50 mg, 0.10 mmol) in EtOAc (8 mL).…”

Section: Organic and Biomolecular Chemistry Papermentioning

confidence: 99%

A case study of the MAC (masked acyl cyanide) oxyhomologation of N,N-dibenzyl-l-phenylalaninal with anti diastereoselectivity: preparation of (2S,3S)-allophenylnorstatin esters

Buchotte

Guillot

et al. 2022

Org. Biomol. Chem.

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“…C99, a membrane-bound carboxyl-terminal fragment (CTF), remains attached to the structure. To lower the Aβ levels, BACE1 activity must be reduced [ 67 , 68 ].…”

Section: Targets Of Alzheimer’s Diseasementioning

confidence: 99%

Advances on Therapeutic Strategies for Alzheimer’s Disease: From Medicinal Plant to Nanotechnology

et al. 2022

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Alzheimer’s disease (AD) is a chronic dysfunction of neurons in the brain leading to dementia. It is characterized by gradual mental failure, abnormal cognitive functioning, personality changes, diminished verbal fluency, and speech impairment. It is caused by neuronal injury in the cerebral cortex and hippocampal area of the brain. The number of individuals with AD is growing at a quick rate. The pathology behind AD is the progress of intraneuronal fibrillary tangles, accumulation of amyloid plaque, loss of cholinergic neurons, and decrease in choline acetyltransferase. Unfortunately, AD cannot be cured, but its progression can be delayed. Various FDA-approved inhibitors of cholinesterase enzyme such as rivastigmine, galantamine, donepezil, and NDMA receptor inhibitors (memantine), are available to manage the symptoms of AD. An exhaustive literature survey was carried out using SciFinder’s reports from Alzheimer’s Association, PubMed, and Clinical Trials.org. The literature was explored thoroughly to obtain information on the various available strategies to prevent AD. In the context of the present scenario, several strategies are being tried including the clinical trials for the treatment of AD. We have discussed pathophysiology, various targets, FDA-approved drugs, and various drugs in clinical trials against AD. The goal of this study is to shed light on current developments and treatment options, utilizing phytopharmaceuticals, nanomedicines, nutraceuticals, and gene therapy.

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“…Because the distance between the flap domain and the cleft domain that forms the S 2 pocket of BACE1 was narrow, a planar aromatic ring, such as an isophthalic scaffold, might dock closely in the S 2 pocket of BACE1. Hence, we designed a series of BACE1 inhibitors from the virtual inhibitor 28 (Figure 8), in which the P 2 moiety of our peptidic inhibitors was replaced with an isophthalic scaffold [31][32][33][34][35]. First, we focused on the sterically hindered interaction between the P 3 amide and a proton on the P 2 -isophthalic ring of the virtual inhibitor, which restricts the configuration.…”

Section: Design Of Small-sized Non-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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Novel BACE1 inhibitors with a non-acidic heterocycle at the P1′ position

Cited by 13 publications

References 38 publications

A case study of the MAC (masked acyl cyanide) oxyhomologation of N,N-dibenzyl-l-phenylalaninal with anti diastereoselectivity: preparation of (2S,3S)-allophenylnorstatin esters

A case study of the MAC (masked acyl cyanide) oxyhomologation of N,N-dibenzyl-l-phenylalaninal with anti diastereoselectivity: preparation of (2S,3S)-allophenylnorstatin esters

Advances on Therapeutic Strategies for Alzheimer’s Disease: From Medicinal Plant to Nanotechnology

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

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