Design, synthesis and SAR analysis of potent BACE1 inhibitors: Possible lead drug candidates for Alzheimer's disease

Tarazi, Hamadeh; Odeh, Raed; Al‐Qawasmeh, Raed A.; Yousef, Imad Abu; Voelter, Wolfgang; Al‐Tel, Taleb H.

doi:10.1016/j.ejmech.2016.11.021

Cited by 24 publications

(13 citation statements)

References 32 publications

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“…The traditional medicinal chemistry strategies followed in this study, such as rigidification, contraction, and bioisostere replacement led to the development of BACE1 inhibitors with high potencies . Scheme illustrates the main strategies utilized to design and develop a series of BACE1 inhibitors with improved affinity and inhibition activity . The most potent compound of this series (compound 9) , exhibited a BACE1 IC 50 of 18 nM, with enhanced selectivity toward BACE1 over BACE2 …”

Section: Bace1 As a Potential Target For The Treatment Of Alzheimer'smentioning

confidence: 99%

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BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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Section: Bace1 As a Potential Target For The Treatment Of Alzheimer'smentioning

confidence: 99%

“…39,63 Scheme 1 illustrates the main strategies utilized to design and develop a series of BACE1 inhibitors with improved affinity and inhibition activity. 64 The most potent compound of this series…”

mentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

Self Cite

226

175

View full text Add to dashboard Cite

show abstract

“…Similarly, and more recently, Tarazi et al 273 carried out detailed QSAR studies on pharmacophoric model based on isophthalic acid scaffolds, which resulted in improvement of ligand affinity for the BACE1 enzyme that were corroborated via IC 50 analysis. Hence, they were able to efficiently design small collections of potent BACE1 inhibitors that could cross the BBB.…”

Section: Ligand-based Virtual Screeningmentioning

confidence: 92%

“…Based on the QSAR studies of frentizole and benzothiazole‐urea derivatives, the authors further designed and synthesized novel small drug molecules which might have the capacity to cross the BBB and inhibit Aβ‐ABAD interaction. Similarly, and more recently, Tarazi et al carried out detailed QSAR studies on pharmacophoric model based on isophthalic acid scaffolds, which resulted in improvement of ligand affinity for the BACE1 enzyme that were corroborated via IC 50 analysis. Hence, they were able to efficiently design small collections of potent BACE1 inhibitors that could cross the BBB.…”

Section: Roles Of Computational Approaches For Targeting Secretasesmentioning

confidence: 94%

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

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“…Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by memory loss and progressive impairment in cognitive functions. To date, no cure has been found that stops or reverses the underlying progression of the disease 1 . Although the cause of AD remains unknown, three main hypotheses have been developed that define the neuropathological profile of this disease.…”

Section: Introductionmentioning

confidence: 99%

Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3

Sciú

Sebastián-Pérez

Martínez-González

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Numerous studies have highlighted the implications of the glycogen synthase kinase 3 (GSK-3) in several processes associated with Alzheimer’s disease (AD). Therefore, GSK-3 has become a crucial therapeutic target for the treatment of this neurodegenerative disorder. Hereby, we report the design and multistep synthesis of ethyl 4-oxo-pyrazolo[4,3-d][1–3]triazine-7-carboxylates and their biological evaluation as GSK-3 inhibitors. Molecular modelling studies allow us to develop this new scaffold optimising the chemical structure. Potential binding mode determination in the enzyme and the analysis of the key features in the catalytic site are also described. Furthermore, the ability of pyrazolotriazinones to cross the blood–brain barrier (BBB) was evaluated by passive diffusion and those who showed great GSK-3 inhibition and permeation to the central nervous system (CNS) showed neuroprotective properties against tau hyperphosphorylation in a cell-based model. These new brain permeable pyrazolotriazinones may be used for key in vivo studies and may be considered as new leads for further optimisation for the treatment of AD.

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Design, synthesis and SAR analysis of potent BACE1 inhibitors: Possible lead drug candidates for Alzheimer's disease

Cited by 24 publications

References 32 publications

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3

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