Design and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 Substituents

Sandgren, Veronica; Bäck, Marcus; Kvarnström, Ingemar; Dahlgren, Anna

doi:10.2174/1874104501307010001

Cited by 25 publications

(8 citation statements)

References 18 publications

(23 reference statements)

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“…The most potent compound among the 30 compounds developed in this series was compound 3 that exhibited a remarkable IC 50 value of 69 nM. 55 This compound possesses bulkier substituents on the hydroxyethelene skeleton compared with other compounds in the same series, which indicated that the binding site of the enzyme at P1 and P3 dispositions could accommodate such large moieties. Nonetheless, this promising activity was not supported by the cell binding assay results that showed a very low percentage of inhibition (ca.…”

Section: Peptidomimetic Bace1 Inhibitorsmentioning

confidence: 90%

“…In other work, a series of hydoxyethylene‐based compounds were synthesized with the aim to discover the potential interactions with BACE1 S1 and S3 binding subpockets. The most potent compound among the 30 compounds developed in this series was compound 3 that exhibited a remarkable IC 50 value of 69 nM . This compound possesses bulkier substituents on the hydroxyethelene skeleton compared with other compounds in the same series, which indicated that the binding site of the enzyme at P1 and P3 dispositions could accommodate such large moieties.…”

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

confidence: 93%

“…3%) of Aβ. This weak activity might be due to the polar amide residues contained in this compound and its high molecular weight which might be limiting factors that affected its cell permeability …”

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

confidence: 99%

“…This weak activity might be due to the polar amide residues contained in this compound and its high molecular weight which might be limiting factors that affected its cell permeability. 55 Other important work from Chang et al, 56 focused also on the design of potent BACE1 inhibitors based on the hydroxyethylamine (HEA). For example, compound 4 with a 3-methoxybenzyl group at P1, and phenylalanine side chain at P1′ showed a subnanomolar IC 50 of 1.0 nM.…”

Section: Peptidomimetic Bace1 Inhibitorsmentioning

confidence: 99%

See 3 more Smart Citations

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

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

211

175

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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: Peptidomimetic Bace1 Inhibitorsmentioning

confidence: 90%

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

confidence: 93%

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

confidence: 99%

Section: Peptidomimetic Bace1 Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

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

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

211

175

View full text Add to dashboard Cite

show abstract

“…In an effort to increase cell permeability by reducing polarity, compound 35 was designed. 142 Despite the rather large lipophilic P1 ligand, this compound showed a BACE1 IC 50 of 69 nM. Unfortunately, this compound did not display cellular potency.…”

Section: Design Of Peptidomimetic Bace1 Inhibitorsmentioning

confidence: 94%

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

2014

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BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's Disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes. BACE1 inhibition has direct implications in the Alzheimer's Disease pathology without largely affecting viability. However, inhibiting BACE1 selectively in vivo has presented many challenges to medicinal chemists. Since its identification in 2000, inhibitors covering many different structural classes have been designed and developed. These inhibitors can be largely classified as either peptidomimetic or non-peptidic inhibitors. Progress in these fields resulted in inhibitors that contain many targeted drug-like characteristics. In this review, we describe structure-based design strategies and evolution of a wide range of BACE1 inhibitors including compounds that have been shown to reduce brain Aβ, rescue the cognitive decline in transgenic AD mice and inhibitor drug candidates that are currently in clinical trials.

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Pharmacogenomics of Alzheimer’s Disease: Novel Therapeutic Strategies for Drug Development

Cacabelos

Torrellas

et al. 2014

Methods in Molecular Biology

165

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Alzheimer's disease (AD) is a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis, and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. As a complex disorder, AD is a polygenic and multifactorial clinical entity in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions, lead to amyloid deposition, neurofibrillary tangle formation, and premature neuronal death, the major neuropathological hallmarks of AD. Future perspectives for the global management of AD predict that genomics and proteomics may help in the search for reliable biomarkers. In practical terms, the therapeutic response to conventional drugs (cholinesterase inhibitors, multifactorial strategies) is genotype-specific. Genomic factors potentially involved in AD pharmacogenomics include at least five categories of gene clusters: (1) genes associated with disease pathogenesis; (2) genes associated with the mechanism of action of drugs; (3) genes associated with drug metabolism (phase I and II reactions); (4) genes associated with drug transporters; and (5) pleiotropic genes involved in multifaceted cascades and metabolic reactions. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.

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Design and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 Substituents

Cited by 25 publications

References 18 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

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

Pharmacogenomics of Alzheimer’s Disease: Novel Therapeutic Strategies for Drug Development

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