Rational design and synthesis of aminopiperazinones as β-secretase (BACE) inhibitors

Tresadern, Gary; Delgado, Francisco; Delgado, Oscar; Gijsen, Harrie J. M.; Macdonald, Gregor; Moechars, Dieder; Rombouts, Frederik; Alexander, Richard; Spurlino, John; Gool, Michiel Van; Vega, Javier Martínez; Trabanco, Andrés A.

doi:10.1016/j.bmcl.2011.10.050

Cited by 44 publications

(33 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is cleaved by b-site APP cleaving enzyme-1 (BACE-1) followed by subsequent cleavage by the g-secretase complex to form Ab peptides. Since the main culprit of Ab aggregation is the b-secretase (BACE1), the inhibition of this enzyme is believed to play an important role in the prevention of AD (Tresadern et al, 2011). Oxidative stress has been found to elevate BACE1 levels in cultured neurons and animal models (Guglielmotto et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Enhancement of β-secretase inhibition and antioxidant activities oftempeh, a fermented soybean cake through enrichment of bioactive aglycones

Ahmad

Ramasamy

Majeed

et al. 2015

Pharmaceutical Biology

View full text Add to dashboard Cite

Mani (2015) Enhancement of β-secretase inhibition and antioxidant activities of tempeh, a fermented soybean cake through enrichment of bioactive aglycones, Pharmaceutical Biology, 53:5, 758-766, DOI: 10.3109/13880209.2014 Context: Soybean and its fermented products are the most common source of isoflavones in human food.Objective: The present study quantifies the major glycosides and aglycones in soybean and its fermented product tempeh isoflavone extracts. The comparision of antioxidant effects and BACE1 inhibitory activity between the isoflavones of soybean and tempeh were also established. Materials and methods:The major isoflavones such as daidzein and genistein (aglycones), and their sugar conjugates (glycosides) daidzin and genistin in soybean and tempeh isoflavones were quantified using HPLC analysis. Comparative studies on BACE 1 (b-site amyloid precursor protein cleaving enzyme 1 or b-secretase 1) inhibition and free-radical scavenging activities (diphenyl-1-picrylhydrazyl (DPPH) and ferrous ion chelating ability) were conducted.Results: The amount of actives (mg/100 g) in soybean isoflavone compared with tempeh isoflavone is as follows: daidzein 16.72 mg/100 g versus 38.91 mg/100 g, genistein 11.10 mg/ 100 g versus 24.03 mg/100 g, daidzin 6.16 mg/100 g versus 0.69 mg/100 g, and genistin 24.61 mg/100 g versus 6.57 mg/100 g. The IC 50 values of soybean and tempeh isoflavones against BACE1 were 10.87 and 5.47 mg/ml, respectively. The tempeh isoflavone had a more potent DPPH free-radical scavenging activity (IC 50 ¼ 2.67 mg/ml) than the soybean isoflavone (IC 50 ¼ 10 mg/ml). The ferrous ion chelating ability of the isoflavones was practically similar (IC 50 ¼ 10.40 mg/ml, soybean and 11.13 mg/ml, tempeh). Discussion and conclusion: The present study indicates that tempeh is a healthy supplement to alleviate oxidative stress through the enrichment of aglycones.

show abstract

Section: Introductionmentioning

confidence: 99%

Enhancement of β-secretase inhibition and antioxidant activities oftempeh, a fermented soybean cake through enrichment of bioactive aglycones

Ahmad

Ramasamy

Majeed

et al. 2015

Pharmaceutical Biology

View full text Add to dashboard Cite

show abstract

“…Reviews have shown that the physicochemical properties of a successful CNS drug are more restrictive than Lipinski’s rule of five, setting for instance the molecular weight limit at 450, the p K a in the 7.5–10.5 range, and clogP below 5 12. In the BACE1 context, control of the basicity of the amidine moiety is crucial for combining efficient interaction in the active site and blood–brain barrier crossing 13. It is well known that selective introduction of fluorine atoms into organic molecules is a powerful strategy to modify their physicochemical and biological properties 14.…”

Section: Introductionmentioning

confidence: 99%

Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

Calandrini

Nguyen

Arnesano

et al. 2014

Chemistry A European J

View full text Add to dashboard Cite

Cisplatin is one of the most used anticancer drugs. Its cellular influx and delivery to target DNA may involve the copper chaperone Atox1 protein. Although the mode of binding is established by NMR spectroscopy measurements in solution-the Pt atom binds to Cys12 and Cys15 while retaining the two ammine groups-the structural determinants of the adduct are not known. Here a structural model by hybrid Car-Parrinello density functional theory-based QM/MM simulations is provided. The platinated site minimally modifies the fold of the protein. The calculated NMR and CD spectral properties are fully consistent with the experimental data. Our in silico/in vitro approach provides, together with previous studies, an unprecedented view into the structural biology of cisplatin-protein adducts.

show abstract

“…Aminopiperazinone inhibitors of β-secretase were identified by rational design by Tresadern and collaborators [100]. The initial racemic hit 58 (Fig.…”

Section: Small-molecule β-Secretase Inhibitorsmentioning

confidence: 99%

“…At 60 mg/kg subcutaneous dose it was showed a reduction of Aβ by 48%, 67% and 73% at 1, 2 and 4 h respectively. However, these molecules showed a rapid decrease in plasma concentration levels, likely due to low metabolic stability [100]. …”

Section: Small-molecule β-Secretase Inhibitorsmentioning

confidence: 99%

The Structural Evolution of β-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors

Butini¹,

Brogi²,

Novellino³

et al. 2013

CTMC

View full text Add to dashboard Cite

Effective treatment of Alzheimer’s disease (AD) remains a critical unmet need in medicine. The lack of useful treatment for AD led to an intense search for novel therapies based on the amyloid hypothesis, which states that amyloid β-42 (Aβ42) plays an early and crucial role in all cases of AD. β-Secretase (also known as BACE-1 β-site APP-cleaving enzyme, Asp-2 or memapsin-2) is an aspartyl protease representing the rate limiting step in the generation of Aβ peptide fragments, therefore it could represent an important target in the steady hunt for a disease-modifying treatment. Generally, β-secretase inhibitors are grouped into two families: peptidomimetic and nonpeptidomimetic inhibitors. However, irrespective of the class, serious challenges with respect to blood–brain barrier (BBB) penetration and selectivity still remain. Discovering a small molecule inhibitor of β-secretase represents an unnerving challenge but, due to its significant potential as a therapeutic target, growing efforts in this task are evident from both academic and industrial laboratories. In this frame, the rising availability of crystal structures of β-secretase-inhibitor complexes represents an invaluable opportunity for optimization. Nevertheless, beyond the inhibitory activity, the major issue of the current research approaches is about problems associated with BBB penetration and pharmacokinetic properties. This review follows the structural evolution of the early β-secretase inhibitors and gives a snap-shot of the hottest chemical templates in the literature of the last five years, showing research progress in this field.

show abstract

Rational design and synthesis of aminopiperazinones as β-secretase (BACE) inhibitors

Cited by 44 publications

References 36 publications

Enhancement of β-secretase inhibition and antioxidant activities oftempeh, a fermented soybean cake through enrichment of bioactive aglycones

Enhancement of β-secretase inhibition and antioxidant activities oftempeh, a fermented soybean cake through enrichment of bioactive aglycones

Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

The Structural Evolution of β-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors

Contact Info

Product

Resources

About

Rational design and synthesis of aminopiperazinones as β-secretase (BACE) inhibitors

Cited by 44 publications

References 36 publications

Enhancement of β-secretase inhibition and antioxidant activities oftempeh, a fermented soybean cake through enrichment of bioactive aglycones

Enhancement of β-secretase inhibition and antioxidant activities oftempeh, a fermented soybean cake through enrichment of bioactive aglycones

Structural Biology of Cisplatin Complexes with Cellular Targets: The Adduct with Human Copper Chaperone Atox1 in Aqueous Solution

The Structural Evolution of &#946;-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors

Contact Info

Product

Resources

About

The Structural Evolution of β-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors