WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H522439
CAS#: 1227163-84-9
Description: AZD3839 is a potent and selective BACE1 inhibitor. AZD3839 is clinical candidate for the treatment of Alzheimer disease. AZD3839 inhibits BACE1 activity, Aβ and sAPPβ 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 exhibits dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in mouse, guinea pig, and non-human primate. AZD3839 effectively reduces the levels of Aβ in brain, CSF, and plasma in several preclinical species.
Hodoodo Cat#: H522439
Name: AZD3839
CAS#: 1227163-84-9
Chemical Formula: C24H16F3N5
Exact Mass: 431.14
Molecular Weight: 431.422
Elemental Analysis: C, 66.82; H, 3.74; F, 13.21; N, 16.23
Synonym: AZD3839; AZD-3839; AZD 3839.
IUPAC/Chemical Name: (S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine
InChi Key: MRXBCEQZNKUUIP-DEOSSOPVSA-N
InChi Code: 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
SMILES Code: NC1=N[C@@](C2=CC=CC(C3=CN=CN=C3)=C2)(C4=CC(C(F)F)=NC=C4)C5=C1C(F)=CC=C5
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | AZD3839 is a BACE1 inhibitor with an IC50 of 23.6 uM. |
| In vitro activity: | The potency of AZD3839 to inhibit BACE1 and its closely related enzymes was evaluated in vitro (Table 2). In a concentration-dependent manner, AZD3839 reached 100% inhibition of recombinant human BACE1 cleavage of a 10-amino acid-long swe-mutation APP sequence, with a resulting Ki of 26.1 nmol/liter. The potency to inhibit BACE2 was 14-fold higher (Ki = 372 nmol/liter). AZD3839 showed more than a 1000-fold selectivity against the aspartic protease cathepsin D (Ki>25 μmol/liter). In SH-SY5Y cells overexpressing APP695wt, AZD3839 efficiently decreased the Aβ40 levels in a concentration-dependent manner with a resulting IC50 of 4.8 nmol/liter. AZD3839 also efficiently decreased the formation of sAPPβ in SH-SY5Y cells with an IC50 of 16.7 nmol/liter. In a similar fashion AZD3839 decreased the Aβ40 levels secreted from C57BL/6 mouse primary cortical neurons, N2A cells (mouse neuroblastoma), and Dunkin-Hartley guinea pig primary cortical neurons, resulting in IC50 values of 50.9, 32.2, and 24.8 nmol/liter, respectively. Hence, based on Aβ40 readout, AZD3839 was nine times more potent in the human cell assay compared with the average of the two mouse cellular assays. Reference: J Biol Chem. 2012 Nov 30;287(49):41245-57. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510823/ |
| In vivo activity: | In C57BL/6 mice, orally administrated AZD3839 gave a dose- and time-dependent reduction of plasma and brain Aβ (Fig. 3). Brain concentrations of AZD3839 increased rapidly and peaked at 0.5 h after dosing 80 μmol/kg AZD3839, the earliest observation time point. Brain Aβ40 levels decreased ∼30% versus vehicle at 1.5 h after dose and returned to base line after 4.5 h. A higher dose of AZD3839 (160 μmol/kg) led to increased brain concentrations and consequently a more pronounced and long-lasting reduction (∼50% versus vehicle) that returned to base line after 8 h (Fig. 3A). The levels of brain Aβ42 (Fig. 3B) and sAPPβ followed the same pattern as Aβ40. In addition, both doses of AZD3839 reduced plasma levels of Aβ40 by ∼60% versus vehicle over a prolonged period (Fig. 3C). At 8 h after administration, the inhibitory effect started to decline within the low dose group, whereas maximal efficacy was maintained within the high dose group. Reference: J Biol Chem. 2012 Nov 30;287(49):41245-57. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510823/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMF | 2.0 | 4.64 | |
| DMSO | 80.3 | 186.20 | |
| Ethanol | 58.0 | 134.44 | |
| Ethanol:PBS (pH 7.2) (1:1) | 0.5 | 1.16 |
The following data is based on the product molecular weight 431.42 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Jeppsson F, 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. doi: 10.1074/jbc.M112.409110. Epub 2012 Oct 9. PMID: 23048024; PMCID: PMC3510823. |
| In vitro protocol: | 1. Jeppsson F, 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. doi: 10.1074/jbc.M112.409110. Epub 2012 Oct 9. PMID: 23048024; PMCID: PMC3510823. |
| In vivo protocol: | 1. Jeppsson F, 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. doi: 10.1074/jbc.M112.409110. Epub 2012 Oct 9. PMID: 23048024; PMCID: PMC3510823. |
1: Sparve E, Quartino AL, Lüttgen M, Tunblad K, Gårdlund AT, Fälting J, Alexander R, Kågström J, Sjödin L, Bulgak A, Al-Saffar A, Bridgland-Taylor M, Pollard C, Swedberg MD, Vik T, Paulsson B. 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. doi: 10.1124/jpet.114.215202. Epub 2014 Jun 10. PubMed PMID: 24917547.
2: Lindgren A, Eklund G, Turek D, Malmquist J, Swahn BM, Holenz J, von Berg S, Karlström S, Bueters T. Biotransformation of two β-secretase inhibitors including ring opening and contraction of a pyrimidine ring. Drug Metab Dispos. 2013 May;41(5):1134-47. doi: 10.1124/dmd.112.050351. Epub 2013 Mar 8. PubMed PMID: 23474650.
3: Aasa J, Hu Y, Eklund G, Lindgren A, Baranczewski P, Malmquist J, Turek D, Bueters T. Effect of solvents on the time-dependent inhibition of CYP3A4 and the biotransformation of AZD3839 in human liver microsomes and hepatocytes. Drug Metab Dispos. 2013 Jan;41(1):159-69. doi: 10.1124/dmd.112.047597. Epub 2012 Oct 16. PubMed PMID: 23073735.
4: Jeppsson F, 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. doi: 10.1074/jbc.M112.409110. Epub 2012 Oct 9. PubMed PMID: 23048024; PubMed Central PMCID: PMC3510823.
5: Swahn BM, Kolmodin K, Karlström S, von Berg S, Söderman P, Holenz J, Berg S, Lindström J, Sundström M, Turek D, Kihlström J, Slivo C, Andersson L, Pyring D, Rotticci D, Ohberg L, Kers A, Bogar K, von Kieseritzky F, Bergh M, Olsson LL, Janson J, Eketjäll S, Georgievska B, Jeppsson F, Fälting J. Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides. J Med Chem. 2012 Nov 8;55(21):9346-61. doi: 10.1021/jm3009025. Epub 2012 Sep 17. PubMed PMID: 22924815.
