A Phase I, Randomised, Double-blind, Placebo-controlled, Parallel-group Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Biomarkers of AZD3839 Including an Open-label Food Effect Group in Healthy Male and Female Volunteers of Non-childbearing Potential

The purpose of the study is to assess the safety, tolerability and blood concentration of AZD3839 following oral administration of single doses in healthy men and women of non-childbearing potential

Start Date01 Jun 2011

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with AZD-3839

100 Translational Medicine associated with AZD-3839

100 Patents (Medical) associated with AZD-3839

Literatures (Medical) associated with AZD-3839

24 May 2021·Journal of Biomolecular Structure and Dynamics

A series of molecular modeling techniques to reveal selective mechanisms of inhibitors to β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) and β-site amyloid precursor protein cleaving enzyme 2 (BACE2)

Article

Author: Li, Shipeng ; Yu, Hualin ; Li, Jinghui ; Zhao, Hexiang ; Hao, Jiajia

Inhibition of β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) has been shown to be an effective treatment for Alzheimer's disease. A wealth of research has focused on finding highly selective small-molecule inhibitors targeting the BACE1 over its close homologue BACE2 to avoid potential side effects. However, given the highly structural similarities of BACE1 and BACE2, designing highly selective BACE1 inhibitors remains a huge challenge. Recently, it has been reported that a potential BACE1 inhibitor named C28 (∼52-fold selectivity) exhibited greater selectivity to BACE1 over BACE2 than the previously reported inhibitors AZD3293 and AZD3839 (∼1.5-fold and 14-fold selectivity). However, few computational studies have been performed to reveal its underlying mechanisms. In this study, a series of molecular modeling techniques were performed to reveal the selective mechanisms. Classical molecular dynamics (cMD) simulations indicated that the major variations appeared to be controlled by overall protein dynamics. Free energy calculations further suggested that the binding affinities of AZD3293 to BACE1 and BACE2 are similar, but the binding affinity of AZD3839 and C28 to BACE1 is much higher than to BACE2, and that the major variations are electrostatic interactions. The protein dynamics and energy differences were further observed in accelerated molecular dynamics (aMD) simulations. In addition, the umbrella sampling simulations revealed the inhibitors' different patterns of dissociation from the binding pockets of BACE1 and BACE2, and that different energy barriers were responsible for the selectivity. The physical principles revealed by this study may facilitate the rational design of more potent BACE1 selective inhibitors. Communicated by Ramaswamy H. Sarma.

01 Nov 2017·Analytical and Bioanalytical ChemistryQ2 · CHEMISTRY

A microfluidics-based mobility shift assay to identify new inhibitors of β-secretase for Alzheimer’s disease

Q2 · CHEMISTRY

Article

Author: Liu, Rongfeng ; Zhu, Haiyan ; Zhang, Xuehong ; Liu, Yu-Chih ; Meng, Junwei

The β-secretase (BACE1) initiates the generation of toxic amyloid-β peptide (Aβ) from amyloid-β precursor protein (APP), which was widely considered to play a key role in the pathogenesis of Alzheimer's disease (AD). Here, a novel microfluidics-based mobility shift assay (MMSA) was developed, validated, and applied for the screening of BACE1 inhibitors for AD. First, the BACE1 activity assay was established with a new fluorescent peptide substrate (FAM-EVNLDAEF) derived from the Swedish mutant APP, and high-quality ratiometric data were generated in both endpoint and kinetic modes by electrophoretic separation of peptide substrate from the BACE1 cleaved product (FAM-EVNL) before fluorescence quantification. To validate the assay, the inhibition and kinetic parameter values of two known inhibitors (AZD3839 and AZD3293) were evaluated, and the results were in good agreement with those reported by other methods. Finally, the assay was applied to screen for new inhibitors from a 900-compound library in a 384-well format, and one novel hit (IC₅₀ = 26.5 ± 1.5 μM) was identified. Compared with the common fluorescence-based assays, the primary advantage of the direct MMSA was to discover novel BACE1 inhibitors with lower auto-fluorescence interference, and its superb capability for kinetic study. Graphical abstract Microfluidics-based mobility shift assay for BACE1.

01 Sep 2014·Clinical Pharmacology in Drug DevelopmentQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: Alexander, Robert ; Bueters, Tjerk ; Quartino, Angelica ; Karlsson, Pär ; Fälting, Johanna ; Lüttgen, Maria ; Sparve, Erik ; Lee, Chi‐Ming ; Paulsson, Björn ; Maltby, Justine ; Claeson‐Bohnstedt, Kristina ; Paraskos, Jonathan ; Huledal, Gunilla ; Olsson, Tina

AbstractModulating 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.

100 Deals associated with AZD-3839

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 3	GB	AstraZeneca PLC	01 Jun 2011
Valinemia	Phase 3	GB	AstraZeneca PLC	01 Jun 2011

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