Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model

Truong, Anh P.; Toth, G.; Probst, Gary D.; Sealy, Jennifer M.; Bowers, Simeon; Wone, David W.G.; Dressen, Darren; Hom, Roy K.; Konradi, Andrei W.; Sham, Hing L.; Wu, Jing; Peterson, Brian; Ruslim, Lany; Bova, Michael P.; Kholodenko, Dora; Motter, Ruth; Bard, Frédérique; Santiago, Pamela; Ni, Huifang; Chian, David; Soriano, Ferdie; Cole, Tracy; Brigham, Elizabeth F.; Wong, Karina; Zmolek, Wes; Goldbach, Erich; Samant, Bhushan; Chen, Linda; Zhang, Hongbing; Nakamura, David; Quinn, Kevin P.; Yednock, Ted; Sauer, John‐Michael

doi:10.1016/j.bmcl.2010.08.102

Cited by 44 publications

(22 citation statements)

References 91 publications

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“…After many SAR studies and rounds of optimization aimed specifically at improving permeability and decreasing Pgp efflux rate, they have recently reported a HEA derivative, (8) as illustrated in Fig. (1), which can lower A levels in the brain and CSF of an animal model [51]. This compound is comprised of a difluoroaryl group in P1, a cyclopropyl group in P1' and a polar aryl in P2'.…”

Section: Hea and Diamine Derivativesmentioning

confidence: 98%

BACE Inhibitors as Potential Drugs for the Treatment of Alzheimers Disease: Focus on Bioactivity

Evin¹,

Lessène²,

Wilkins

2011

RPCN

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Current drug development for the treatment of Alzheimer's Disease is principally based on the amyloid cascade theory, and aims to reduce the levels of Aβ amyloid peptide in the brain. This can be achieved, either by decreasing peptide production through inhibition of β-secretase (also known as BACE-1) or γ-secretase, or by interfering with Aβ aggregation, or by promoting Aβ clearance. Targeting BACE-1, the proteolytic enzyme that initiates Aβ formation, has generated a lot of research interest recently and is currently thought to be one of the most promising therapeutic approaches. In this review, we summarize and discuss the latest patents and publications describing BACE-1 inhibitors, principally focussing on their drug properties and performance in preclinical trials.

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Section: Hea and Diamine Derivativesmentioning

confidence: 98%

BACE Inhibitors as Potential Drugs for the Treatment of Alzheimers Disease: Focus on Bioactivity

Evin¹,

Lessène²,

Wilkins

2011

RPCN

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“…76 Orally effective HEA derivatives were shown to have a significant BACE1 inhibition in a preclinical animal model. 77 TAK-070, a novel nonpeptide BACE1 inhibitor compound was developed by Takeda Pharmaceuticals Japan, demonstrated significant Ab lowering activity in a mouse model. 78 Another compound AZD3293, a BACE1 inhibitor by Astra Zeneca (London, UK), is presently in a Phase 1 clinical trial.…”

Section: Tau Proteinmentioning

confidence: 99%

Current and novel therapeutic molecules and targets in Alzheimer's disease

Kumar

Nisha

Silakari

et al. 2016

Journal of the Formosan Medical Association

126

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Alzheimer's disease (AD) is a neurodegenerative disorder in which the death of brain cells causes memory loss and cognitive decline, i.e., dementia. The disease starts with mild symptoms and gradually becomes severe. AD is one of the leading causes of mortality worldwide. Several different hallmarks of the disease have been reported such as deposits of β-amyloid around neurons, hyperphosphorylated tau protein, oxidative stress, dyshomeostasis of bio-metals, low levels of acetylcholine, etc. AD is not simple to diagnose since there is no single diagnostic test for it. Pharmacotherapy for AD currently provides only symptomatic relief and mostly targets cognitive revival. Computational biology approaches have proved to be reliable tools for the selection of novel targets and therapeutic ligands. Molecular docking is a key tool in computer-assisted drug design and development. Docking has been utilized to perform virtual screening on large libraries of compounds, and propose structural hypotheses of how the ligands bind with the target with lead optimization. Another potential application of docking is optimization stages of the drug-discovery cycle. This review summarizes the known drug targets of AD, in vivo active agents against AD, state-of-the-art docking studies done in AD, and future prospects of the docking with particular emphasis on AD.

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“…Replacement of the secondary benzylamino group with a phenylcyclopropylamino group, enhanced potency and reduced BACE-1, Pgp-mediated efflux leading to better brain permeation (Lerchner et al, 2010). The aryl linker region of orally efficacious hydroxyethylamine BACE-1 inhibitors were reported after a series of compounds were designed, which showed highly permeability coupled with negligible levels of Pgp activity Truong et al, 2010). Using a 1,4-dihydropyridine scaffold, new inhibitors of BACE-1 were synthesized by modifying the known BACE inhibitor 2 containing a hydroxyethylamine motif.…”

Section: Bace 1 Inhibitorsmentioning

confidence: 99%

The Recent Updates of Therapeutic Approaches Against Aβ for the Treatment of Alzheimer's Disease

Shao

Zhou

Rudd

et al. 2011

The Anatomical Record

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One of the main neuropathological lesions observed in brain autopsy of Alzheimer's disease (AD) patients is the extracellular senile plaques mainly composed of amyloid-beta (Ab) peptide. Recently, treatment strategies have focused on modifying the formation, clearance, and accumulation of this potentially neurotoxic peptide. b-and c-secretase are responsible for the cleavage of amyloid precursor protein (APP) and the generation of Ab peptide. Treatments targeting these two critical secretases may therefore reduce Ab peptide levels and positive impact on AD. Vaccination is also an advanced approach against Ab. This review focuses on recent advances of our understanding of this key peptide, with emphasis on Ab peptide synthesis, accumulation and neurotoxicity, and current therapies including vaccination and two critical secretase inhibitors. MicroRNAs (miRNAs) are a class of conserved endogenous small noncoding RNAs, known to regulate the expression of complementary messenger RNAs, involved in AD development. We therefore address the relationship of miRNAs in the brain and Ab generation, as a novel therapeutic approach to the treatment of AD while also providing new insights on the etiology of this neurological disorder. Anat Rec, 294:1307Rec, 294: -1318Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.

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Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model

Cited by 44 publications

References 91 publications

BACE Inhibitors as Potential Drugs for the Treatment of Alzheimers Disease: Focus on Bioactivity

BACE Inhibitors as Potential Drugs for the Treatment of Alzheimers Disease: Focus on Bioactivity

Current and novel therapeutic molecules and targets in Alzheimer's disease

The Recent Updates of Therapeutic Approaches Against Aβ for the Treatment of Alzheimer's Disease

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