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4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine

BACE1 inhibitor,potent and selective CAS# 1227163-56-5

4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine

Catalog No. BCC5113----Order now to get a substantial discount!

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Chemical structure

4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine

3D structure

Chemical Properties of 4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine

Cas No. 1227163-56-5 SDF Download SDF
PubChem ID 122173005 Appearance Powder
Formula C24H15F4N5 M.Wt 449.4
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble in DMSO
Chemical Name (3S)-7-fluoro-3-(3-pyrimidin-5-ylphenyl)-3-[2-(trifluoromethyl)pyridin-4-yl]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)F)C5=CN=CN=C5
Standard InChIKey KJPBADHCKFUMIL-QHCPKHFHSA-N
Standard InChI InChI=1S/C24H15F4N5/c25-19-6-2-5-18-21(19)22(29)33-23(18,17-7-8-32-20(10-17)24(26,27)28)16-4-1-3-14(9-16)15-11-30-13-31-12-15/h1-13H,(H2,29,33)/t23-/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 4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine

DescriptionAZD3839 is a novel inhibitor of BACE1 with IC50 value of 4.8μM
TargetsBACE1    

4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine Dilution Calculator

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4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine Molarity Calculator

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Preparing Stock Solutions of 4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2252 mL 11.1259 mL 22.2519 mL 44.5038 mL 55.6297 mL
5 mM 0.445 mL 2.2252 mL 4.4504 mL 8.9008 mL 11.1259 mL
10 mM 0.2225 mL 1.1126 mL 2.2252 mL 4.4504 mL 5.563 mL
50 mM 0.0445 mL 0.2225 mL 0.445 mL 0.8901 mL 1.1126 mL
100 mM 0.0223 mL 0.1113 mL 0.2225 mL 0.445 mL 0.5563 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 4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine

AZD3839 is a novel inhibitor of BACE1 with IC50 value of 4.8μM [1].

AZD3839 has been reported to inhibit human BACE1 activity in a biochemical FRET assay. In addition, AZD3839 has also been reported to inhibit the release of sAPPβs from human SH-SY5Y cells, mouse N2A cells and mouse and guinea pig primary cortical neurons. Moreover, AZD3839 has been revealed to effectively decrease the cerebrospinal fluid (CSF), plasma, and brain Aβ levels in guinea pig, mouse and non-human primate. AZD3839 has also been revealed to decrease the levels of Aβ40 secreted from C57BL/6 mouse primary cortical neurons, N2A cells (mouse neuroblastoma), and Dunkin-Hartley guinea pig primary cortical neurons, with IC50 values of 50.9, 32.2, and 24.8 nmol/liter, respectively [2].

References:
[1] Sparve E1, Quartino AL1, Luttgen M1, Tunblad K1, Teiling-Gardlund A1, Falting J1, Alexander R1, Kagstrom J1, Sjodin L1, Bulgak A1, Al-Saffar A1, Bridgland-Taylor M2, Pollard C3, Swedberg MD4, Vik T5, Paulsson B1. 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 Jun 10.
[2] Jeppsson F1, Eketjäll S, Janson J, Karlström S, Gustavsson S, Olsson LL, Radesäter AC, Ploeger B, Cebers G, Kolmodin K, Swahn BM, von Berg S, Bueters T, Fälting 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.

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References on 4-Fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine

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.

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