AZD3839

Potent and selective BACE1 inhibitor CAS# 1227163-84-9

AZD3839

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AZD3839

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Chemical Properties of AZD3839

Cas No. 1227163-84-9 SDF Download SDF
PubChem ID 46202416 Appearance Powder
Formula C24H16F3N5 M.Wt 431.41
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 125 mg/mL (289.75 mM; Need ultrasonic)
Chemical Name (3S)-3-[2-(difluoromethyl)pyridin-4-yl]-7-fluoro-3-(3-pyrimidin-5-ylphenyl)isoindol-1-amine
SMILES C1=CC(=CC(=C1)C2(C3=C(C(=CC=C3)F)C(=N2)N)C4=CC(=NC=C4)C(F)F)C5=CN=CN=C5
Standard InChIKey MRXBCEQZNKUUIP-DEOSSOPVSA-N
Standard InChI InChI=1S/C24H16F3N5/c25-19-6-2-5-18-21(19)23(28)32-24(18,17-7-8-31-20(10-17)22(26)27)16-4-1-3-14(9-16)15-11-29-13-30-12-15/h1-13,22H,(H2,28,32)/t24-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of AZD3839

DescriptionAZD3839 (free base) is a potent and selective BACE1 inhibitor with IC50 of 23.6 uM, about 14-fold selectivity over BACE2, also a β-secretase enzyme inhibitor. target: BACE1, β-secretase enzyme [1] IC50: 23.6 uM [1] AZD3839 dissolved in 0.33% dimethylsulfoxide In vitro: AZD3839 and its metabolites M1 and M2 inhibited CYP3A4 in a reversible and an irreversible manner, which could affect not only the metabolism of other CYP3A4 substrates but also the metabolism of AZD3839 itself. [1] In vivo: AZD3839 is dissolved in 0.3 M gluconic acid, adjusted to pH 3. Solutions of 0.75, 2.5, and 7.5 mg/ml are prepared and are administered orally by gavage at 2 ml/kg body weight at 1.5, 5, and 15 mg/kg (study 1) and 15 mg/kg (study 2). [1]AZD3839 effectively reduces the levels of Aβ in brain, CSF, and plasma in several preclinical species. [2]

References:
[1]. Sparve E et al. Prediction and modeling of effects on the QTc interval for clinical safety margin assessment, based on single-ascending-dose study data with AZD3839. J Pharmacol Exp Ther. 2014 Aug;350(2):469-78. [2]. Jeppsson F et al. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem. 2012 Nov 30;287(49):41245-57.

AZD3839 Dilution Calculator

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Preparing Stock Solutions of AZD3839

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.318 mL 11.5899 mL 23.1798 mL 46.3596 mL 57.9495 mL
5 mM 0.4636 mL 2.318 mL 4.636 mL 9.2719 mL 11.5899 mL
10 mM 0.2318 mL 1.159 mL 2.318 mL 4.636 mL 5.795 mL
50 mM 0.0464 mL 0.2318 mL 0.4636 mL 0.9272 mL 1.159 mL
100 mM 0.0232 mL 0.1159 mL 0.2318 mL 0.4636 mL 0.5795 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on AZD3839

Description:

IC50: 16.7 nM for BACE1

β-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processes of the amyloid precursor protein (APP) and formation of amyloid β peptide (Aβ) species. Because cerebral deposition of Aβ species is possibly critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. AZD3839 is a potent and selective BACE1 inhibitor.

In vitro: AZD3839 concentration-dependently inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer assay, Aβ and sAPPβ release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from guinea pig and mouse primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively [1].

In vivo: AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in mouse, guinea pig, and non-human primate. PK/PD analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects [1].

Clinical trial: Based on the pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man [2].

Reference:
[1] Jeppsson F, Eketj?ll S, Janson J, Karlstr?m S, Gustavsson S, Olsson LL, Rades?ter AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM, von Berg S, Bueters T, F?lting J.  Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem. 2012 Nov 30;287(49):41245-57.
[2] https://clinicaltrials. gov/ct2/show/NCT01348737?term=AZD3839&rank=1

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References on AZD3839

Effect of solvents on the time-dependent inhibition of CYP3A4 and the biotransformation of AZD3839 in human liver microsomes and hepatocytes.[Pubmed:23073735]

Drug Metab Dispos. 2013 Jan;41(1):159-69.

Time-dependent inhibition (TDI) of the cytochrome P450 (P450) family of enzymes is usually studied in human liver microsomes (HLM) by investigating whether the inhibitory potency is increased with increased incubation times. The presented work was initiated after a discrepancy was observed for the TDI of an important P450 enzyme, CYP3A4, during early studies of the investigational drug compound AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H- isoindol-3-amine hemifumarate]; TDI was detected using a regulatory method but not with an early screening method. We show here that the different solvents present in the respective studies, dimethyl sulfoxide (DMSO, screening method) versus methanol or water (regulatory method), were responsible for the different TDI results. We further demonstrate why DMSO, present at the levels of 0.2% and 0.5% in the incubations, masked the TDI effect. In addition to the TDI experiments performed in HLM, TDI studies with AZD3839 were performed in pooled human hepatocytes (Hhep) from different suppliers, using DMSO, methanol, or water. The results from these experiments show no TDI or attenuated TDI effect, depending on the supplier. Metabolite identification of the compound dissolved in DMSO, methanol, or water shows different profiles after incubations with the different systems (HLM or Hhep), which may explain the differences in the TDI outcomes. Thorough investigations of the biotransformation of AZD3839 have been performed to find the reactive pathway causing the TDI of CYP3A4, and are presented here. Our findings show that the in vitro risk profile for drug-drug interactions potential of AZD3839 is very much dependent on the chosen test system and the experimental conditions used.

Population pharmacokinetic and pharmacodynamic analysis of plasma Abeta40 and Abeta42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers.[Pubmed:27129013]

Clin Pharmacol Drug Dev. 2014 Sep;3(5):396-405.

Modulating deposition of Abeta-containing plaques in the brain may be beneficial in treating Alzheimer's disease. beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors have been shown to reduce Abeta in plasma and CSF in healthy volunteers. In this study safety, pharmacokinetics and pharmacodynamics that is reduction of the plasma biomarkers Abeta40 and Abeta42 , 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 Abeta40 and Abeta42 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 Abeta40 and Abeta42 , 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.

Prediction and modeling of effects on the QTc interval for clinical safety margin assessment, based on single-ascending-dose study data with AZD3839.[Pubmed:24917547]

J Pharmacol Exp Ther. 2014 Aug;350(2):469-78.

Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig monophasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to determine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H- isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixed effects modeling, can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the thorough QT/QTc study.

Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease.[Pubmed:23048024]

J Biol Chem. 2012 Nov 30;287(49):41245-57.

beta-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid beta peptide (Abeta) species. Because cerebral deposition of Abeta species might be critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer (FRET) assay, Abeta and sAPPbeta release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Abeta levels in mouse, guinea pig, and non-human primate. Pharmacokinetic/pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduces the levels of Abeta in brain, CSF, and plasma in several preclinical species. It might, therefore, have disease-modifying potential in the treatment of Alzheimer disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.

Description

AZD3839 (free base) is a potent and selective BACE1 inhibitor with IC50 of 23.6 uM, about 14-fold selectivity over BACE2, also a β-secretase enzyme inhibitor.

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