Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer’s disease

Chen, Jian Jeffrey; Liu, Qingyian; Yuan, Chester; Gore, Vijay; Lopez, Patrícia Luciana da Costa; Ma, Vu; Amegadzie, Albert; Qian, Wenyuan; Judd, Ted; Minatti, Ana; Brown, James; Cheng, Yuan; Xue, May; Zhong, Wenge; Dineen, Thomas A.; Epstein, Oleg; Human, Jason; Kreiman, Charles R.; Marx, Isaac E.; Weiss, Matthew M.; Hitchcock, Stephen A.; Powers, Timothy S.; Chen, Kui; Wen, Paul; Whittington, Douglas A.; Cheng, Alan C.; Bartberger, Michael D.; Hickman, Dean; Werner, Jonathan; Vargas, Hugo M.; Everds, Nancy E.; Vonderfecht, Steven; Dunn, Robert T.; Wood, Stephen; Fremeau, Robert T.; White, Ryan D.; Patel, Vinod F.

doi:10.1016/j.bmcl.2014.12.092

Cited by 28 publications

(19 citation statements)

References 25 publications

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“…Studies using animal models have supported the idea that β-secretase inhibitors reduce the amount of amyloid protein in the brain, cerebrospinal fluid (CSF), and plasma [ 50 , 51 ]. A recent study using 2-aminooxazoline and 3-azaxanthenes as BACE inhibitors in a rat model reported a significant reduction in amyloid levels in the brain and CSF [ 52 ]. However, according to Varghese [ 26 ] there are still no inhibitors that have been found to lower Aβ in the brain or CSF in humans.…”

Section: Methodsmentioning

confidence: 99%

Alzheimer’s disease in people with Down’s syndrome: the prospects for and the challenges of developing preventative treatments

2016

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People with Down's syndrome (DS) are at high risk for developing Alzheimer's disease (AD) at a relatively young age. This increased risk is not observed in people with intellectual disabilities for reasons other than DS and for this reason it is unlikely to be due to nonspecific effects of having a neurodevelopmental disorder but, instead, a direct consequence of the genetics of DS (trisomy 21). Given the location of the amyloid precursor protein (APP) gene on chromosome 21, the amyloid cascade hypothesis is the dominant theory accounting for this risk, with other genetic and environmental factors modifying the age of onset and the course of the disease. Several potential therapies targeting the amyloid pathway and aiming to modify the course of AD are currently being investigated, which may also be useful for treating AD in DS. However, given that the neuropathology associated with AD starts many years before dementia manifests, any preventative treatment must start well before the onset of symptoms. To enable trials of such interventions, plasma, CSF, brain, and retinal biomarkers are being studied as proxy early diagnostic and outcome measures for AD. In this systematic review, we consider the prospects for the development of potential preventative treatments of AD in the DS population and their evaluation.

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Section: Methodsmentioning

confidence: 99%

Alzheimer’s disease in people with Down’s syndrome: the prospects for and the challenges of developing preventative treatments

2016

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“…However, this inhibitor has better overlap with both CC1 and CC3, which seems to stabilize the binding mode. Indeed, the recently developed inhibitors reported by Lilly [78] (Figure 3c) and by Amgen [79] (Figure 3d) retain the binding mode of the Schering-Plough compound, making similar interactions with CC1, CC3, CC7 (overlapping with CC1), and CC8.…”

Section: Case Studiesmentioning

confidence: 99%

Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery

Hall

Kozakov

Whitty

et al. 2015

Trends in Pharmacological Sciences

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Analysis of binding energy hot spots at protein surfaces can provide crucial insights into the prospects for successful application of fragment-based drug discovery (FBDD), and whether a fragment hit can be advanced into a high affinity, druglike ligand. The key factor is the strength of the top ranking hot spot, and how well a given fragment complements it. We show that published data are sufficient to provide a sophisticated and quantitative understanding of how hot spots derive from protein three-dimensional structure, and how their strength, number and spatial arrangement govern the potential for a surface site to bind to fragment-sized and larger ligands. This improved understanding provides important guidance for the effective application of FBDD in drug discovery.

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“…Further efforts though SAR generated several potent and orally active BACE1 inhibitors. The compound 3 (listed in Table 1 ) was identified as the most attractive candidate within this series, exhibiting low in vivo clearance, good oral bioavailability, and reduced potential for cardiovascular liabilities in preclinical species (Chen et al, 2015 ).…”

Section: Challenges In Bace1 Inhibitor Developmentmentioning

confidence: 99%

Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment

et al. 2018

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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 target and BACE1 inhibitors have the potential to be disease-modifying drugs for AD treatment. Therefore, intensive efforts to discover and develop inhibitors that can reach the brain and effectively inhibit BACE1 have been pursued by several groups worldwide. The aim of this review is to highlight the progress in the discovery of potent and selective small molecule BACE1 inhibitors over the past decade.

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Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer’s disease

Cited by 28 publications

References 25 publications

Alzheimer’s disease in people with Down’s syndrome: the prospects for and the challenges of developing preventative treatments

Alzheimer’s disease in people with Down’s syndrome: the prospects for and the challenges of developing preventative treatments

Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery

Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment

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