Investigation of α-phenylnorstatine and α-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors (original) (raw)
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Advancements in BACE1 and non-peptide BACE1 inhibitors for Alzheimer’s disease
2018
Numerous theories exist for the pathogenesis of Alzheimer's disease (AD) but BACE1 is considered to be a prime therapeutic target for lowering cerebral Aβ concentrations in Alzheimer's disease and clinical development of BACE1 inhibitors is being intensely pursued. Considering the present scenario, efforts have been put forth to compile all the information relevant to BACE1 and recent developments in the discovery of its non-peptide inhibitors. The upcoming screening methods have been touched upon along with structure based approach for predicting activity of inhibitors of BACE1. This review would aid in research work undertaken by industry and academia as even after decades of earnest research effort, there are relatively few treatment options for patients suffering from Alzheimer's disease.
Bioorganic & Medicinal Chemistry Letters, 2010
The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK a of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Fb production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.
BACE-1 inhibitors Part 1: Identification of novel hydroxy ethylamines (HEAs)
Bioorganic & Medicinal Chemistry Letters, 2008
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.
Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment
Frontiers in chemistry, 2018
Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common type of dementia in the elderly. The clinical symptoms of AD include a progressive loss of memory and impairment of cognitive functions interfering with daily life activities. The main neuropathological features consist in extracellular amyloid-β (Aβ) plaque deposition and intracellular Neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Understanding the pathophysiological mechanisms that underlie neurodegeneration in AD is essential for rational design of neuroprotective agents able to prevent disease progression. According to the "Amyloid Cascade Hypothesis" the critical molecular event in the pathogenesis of AD is the accumulation of Aβ neurotoxic oligomers. Since the proteolytic processing of Amyloid Precursor Protein (APP) by β-secretase (beta-site APP cleaving enzyme 1, BACE1) is the rate-limiting step in the production of Aβ, this enzyme is considered a major therapeutic ...
Preparation and biological evaluation of conformationally constrained BACE1 inhibitors
Bioorganic & Medicinal Chemistry, 2015
The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described.
Recent insight into BACE1 as a potential target for treatment of Alzheimer's disease
2021
Alzheimer's disease (AD) is one of the most common progressive neurodegenerative diseases that represents about 60-80 % of total cases of dementia all over the world. Beta secretase (BACE1) is a membrane-anchored aspartic protease which cleaves the peptide bond between Met671-Asp672 of APP (amyloid precursor protein) where its activity is the rate limiting step of producing amyloid β, the primary neuropathological hallmark of Alzheimer's disease (AD). Therefore, inhibitors of this enzyme have the potential to be a promising and attractive target for intervention of potent therapeutics for treatment AD. Actually, there are many challenges facing the development of effective drug-like BACE1 inhibitors including penetration of BBB and selectivity against other proteases. However, many efforts have been devoted by pharmaceutical industries and academia for development of small size, potent, selective and biologically active BACE1 inhibitors. Till now, none of which is FDA approved but some of which have exhibited clinical potential. In this article, we outlined overview of beta secretase inhibitors that have been designed and developed for treatment of AD.