P1‐335: Novel BACE1 inhibitor, E2609, lowers Aβ levels in the brain, cerebrospinal fluid and plasma in rats and guinea pigs

Fukushima, Tatsuo; Osada, Yoshihide; Ishibashi, Akira; Lucas, Fiona R.

doi:10.1016/j.jalz.2012.05.2021

Cited by 6 publications

(6 citation statements)

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“…Plasma and CSF Aβ were decreased by 90% in monkey and in vivo unbound EC 50 values of 1.3 and 9.5 nM, respectively, were calculated . Also in guinea pigs similar maximal effects were reported in plasma and CSF . Although, no rigorous quantitative analysis was conducted with LY2811376 or E2609, these pre‐clinical data seem to be in line with the results found in humans and support our findings with AZD3839.…”

Section: Discussionsupporting

confidence: 89%

“…25 Also in guinea pigs similar maximal effects were reported in plasma and CSF. 26 Although, no rigorous quantitative analysis was conducted with LY2811376 or E2609, these pre-clinical data seem to be in line with the results found in humans and support our findings with AZD3839. Population PKPD modeling performed herein quantifies the effect on plasma Ab by BACE1 inhibitors in human, which is crucial in order to evaluate the relationship of plasma Ab lowering effect of BACE1 inhibitors across species, information, that is, invaluable for the development of future BACE1 inhibitors.…”

Section: Discussionsupporting

confidence: 86%

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Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ₄₀ and Aβ₄₂ following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Quartino

Huledal

Sparve

et al. 2014

Clinical Pharm in Drug Dev

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Modulating deposition of Aβ-containing plaques in the brain may be beneficial in treating Alzheimer's disease. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors have been shown to reduce Aβ in plasma and CSF in healthy volunteers. In this study safety, pharmacokinetics and pharmacodynamics that is reduction of the plasma biomarkers Aβ40 and Aβ42 , of the BACE1 inhibitor AZD3839 were evaluated. Single oral ascending doses (1-300 mg) of AZD3839 were administered to 54 young healthy volunteers in a randomized, double-blind, placebo-controlled study. The data was analyzed using non-linear mixed effects modeling. AZD3839 reduced Aβ40 and Aβ42 in plasma with estimated potencies (EC50 ) of 46 and 59 nM, respectively, and a maximum effect of approximately 55%. This was in excellent agreement with the concentration-response relationships obtained in mouse and guinea pig. AZD3839 exposure displayed non-linear kinetics, described by a three-compartment model with a saturated binding compartment and an increase in bioavailability with dose. AZD3839 was safe, although, a dose-dependent QTcF prolongation was observed (mean 20 milliseconds at 300 mg). In conclusion, AZD3839 reduced plasma Aβ40 and Aβ42 , demonstrating clinical peripheral proof of mechanism. Pre-clinical models were predictive for the effect of AZD3839 on the human plasma biomarker in a strictly quantitative manner.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 86%

Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ₄₀ and Aβ₄₂ following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Quartino

Huledal

Sparve

et al. 2014

Clinical Pharm in Drug Dev

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show abstract

Section: Resultsmentioning

confidence: 99%

“…As the rate-limiting enzyme of the amyloidogenic processing of amyloid precursor protein (APP), BACE1 is one of the prime targets for AD therapies, with several inhibitors currently undergoing clinical trials33., 34., 35.. BACE1 is largely produced through the translation of the BACE1 mRNA, which cleaves APP to sAPP β and a membrane-bound C-terminal fragment called C99.…”

Section: Resultsmentioning

confidence: 99%

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease

Guo

Zheng

Yang

et al. 2019

Acta Pharmaceutica Sinica B

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Gene therapy represents a promising treatment for the Alzheimer׳s disease (AD). However, gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood–brain barrier (BBB) penetration and QSH peptide for β -amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against β -site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of A β production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the A β deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels, as well as A β and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome.

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“…The compound showed a dose-dependent decrease of up to ∼80% in CSF and up to ∼75% in brain Aβ levels after a single-dose administration to rats and guinea pigs. 116 An impressive and sustained reduction of CSF Aβ 1-40 and Aβ 1-42 levels was also observed in nonhuman primates after oral administration to cynomolgus monkeys. 117 A Phase I trial of E2609 has also been completed successfully, with the compound being well tolerated.…”

Section: Bace1 Inhibitors In Preclinical and Clinical Trialsmentioning

confidence: 86%

Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

Evin

Barakat

2014

DNND

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Alzheimer's disease (AD) is the major cause of dementia in the elderly and an unmet clinical challenge. A variety of therapies that are currently under development are directed to the amyloid cascade. Indeed, the accumulation and toxicity of amyloid-β (Aβ) is believed to play a central role in the etiology of the disease, and thus rational interventions are aimed at reducing the levels of Aβ in the brain. Targeting β-site amyloid precursor protein-cleaving enzyme (BACE)-1 represents an attractive strategy, as this enzyme catalyzes the initial and rate-limiting step in Aβ production. Observation of increased levels of BACE1 and enzymatic activity in the brain, cerebrospinal fluid, and platelets of patients with AD and mild cognitive impairment supports the potential benefits of BACE1 inhibition. Numerous potent inhibitors have been generated, and many of these have been proved to lower Aβ levels in the brain of animal models. Over 10 years of intensive research on BACE1 inhibitors has now culminated in advancing half a dozen of these drugs into human trials, yet translating the in vitro and cellular efficacy of BACE1 inhibitors into preclinical and clinical trials represents a challenge. This review addresses the promises and also the potential problems associated with BACE1 inhibitors for AD therapy, as the complex biological function of BACE1 in the brain is becoming unraveled.

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P1‐335: Novel BACE1 inhibitor, E2609, lowers Aβ levels in the brain, cerebrospinal fluid and plasma in rats and guinea pigs

Cited by 6 publications

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Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ₄₀ and Aβ₄₂ following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ₄₀ and Aβ₄₂ following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease

Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

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P1‐335: Novel BACE1 inhibitor, E2609, lowers Aβ levels in the brain, cerebrospinal fluid and plasma in rats and guinea pigs

Cited by 6 publications

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Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ40 and Aβ42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ40 and Aβ42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease

Critical analysis of the use of &beta;-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer&#39;s disease

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Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ₄₀ and Aβ₄₂ following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ₄₀ and Aβ₄₂ following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers

Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease