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Atabecestat (formerly known as JNJ-54861911) is a novel potent, oral, and brain-penetrant BACE1 inhibitor that inhibits β-site amyloid precursor protein cleaving enzyme 1 (BACE1), an enzyme up-regulated in Alzheimer's disease. β-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer's disease (AD), but treatment initiation may need to be very early. JNJ-54861911 was found to inhibit BACE1 with approximately 2,600 nM affinity to 1 nM affinity. JNJ-54861911 was well-tolerated, adverse events were uncommon and unrelated to JNJ-54861911. JNJ-54861911 showed dose-proportional CSF and plasma pharmacokinetic profiles.
Physicochemical Properties
| Molecular Formula | C18H14FN5OS | |
| Molecular Weight | 367.400064945221 | |
| Exact Mass | 367.09 | |
| CAS # | 1200493-78-2 | |
| Related CAS # | 1200493-78-2;Atabecestat HCl; | |
| PubChem CID | 68254185 | |
| Appearance | White to off-white solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Index of Refraction | 1.681 | |
| LogP | 1.63 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 3 | |
| Heavy Atom Count | 26 | |
| Complexity | 659 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | S1C(N)=N[C@](C=C1)(C)C1C(=CC=C(C=1)NC(C1C=CC(C#N)=CN=1)=O)F |
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| InChi Key | VLLFGVHGKLDDLW-SFHVURJKSA-N | |
| InChi Code | InChI=1S/C18H14FN5OS/c1-18(6-7-26-17(21)24-18)13-8-12(3-4-14(13)19)23-16(25)15-5-2-11(9-20)10-22-15/h2-8,10H,1H3,(H2,21,24)(H,23,25)/t18-/m0/s1 | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
β-site amyloid precursor protein cleaving enzyme 1 (BACE1) [1] - β-site amyloid precursor protein cleaving enzyme 1 (BACE1) [2] |
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| ln Vitro |
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| ln Vivo |
Mice treated with atabecestat (100 and 300 mg/kg; po once daily for 3 days) have lower levels of human Aβ[2]. When APPPS1 mice are treated with 3D6, atabecestat (300 mg/kg; po once) prevents the vascular abnormalities from getting worse[2]. In young and elderly healthy participants who received single and multiple ascending doses of Atabecestat (JNJ-54861911) (up to 14 days), plasma Aβ, CSF Aβ, and CSF-sAPPβ were reduced in a dose-dependent manner, with the maximum Aβ reduction reaching up to 95%. The Aβ reduction effect outlasted the exposure to Atabecestat (JNJ-54861911). APOE ε4 carrier status and baseline Aβ levels did not influence the reductions in Aβ or sAPPβ [1] - In plaque-depositing mice (including transgenic mice) treated with a combination of Atabecestat (JNJ-54861911) (chronic BACE1 inhibitor treatment) and a novel high-affinity antibody against 3pE-modified Aβ, significant clearance of pre-existing amyloid deposits in the brain was achieved without induction of microhemorrhages or other histopathological findings [2] |
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| Animal Protocol |
Animal/Disease Models: 5weeks old APPPS1 mice[2] Doses: 100 and 300 mg/kg Route of Administration: po (oral gavage); 100 and 300 mg/kg; one time/day for 3 days Experimental Results: decreased the level of human Aβ1- 40 and Aβ1-42 levels in the brain of APPPS1 mice at a dose of 300 mg/kg and resulted in less reduction of human Aβ levels at 24 h with a dose of 100 mg/kg. Plaque-depositing mouse model (including transgenic mice) for combination therapy efficacy study: Mice with established plaque deposition were subjected to chronic treatment with Atabecestat (JNJ-54861911) combined with a novel antibody against 3pE-modified Aβ. The specific drug formulation, dissolution method, administration frequency, and route were not provided in the literature. The study evaluated the effect of the combination therapy on amyloid deposit clearance and histopathological changes (such as microhemorrhages) [2] |
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| ADME/Pharmacokinetics |
Atabecestat (JNJ-54861911) exhibited dose-proportional pharmacokinetic profiles in both CSF and plasma of healthy participants after single and multiple dosing [1] |
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| Toxicity/Toxicokinetics |
Atabecestat (JNJ-54861911) was well-tolerated in healthy participants, with uncommon adverse events that were unrelated to the drug [1] - Combination treatment of Atabecestat (JNJ-54861911) with the 3pE-specific antibody did not induce microhemorrhages or other histopathological toxicities in plaque-depositing mice [2] |
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| References |
[1]. Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ-54861911, a potent oral BACE inhibitor.Alzheimers Dement (N Y). 2016 Aug 24;2(3):202-212. [2]. Passive immunotherapy with a novel antibody against 3pE-modified Aβ demonstrates potential for enhanced efficacy and favorable safety in combination with BACE inhibitor treatment in plaque-depositing mice. Neurobiol Dis. 2021 Jul;154:105365. |
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| Additional Infomation |
Atabecestat is under investigation in clinical trial NCT02211079 (A Study to Assess Effect of JNJ-54861911 on Pharmacokinetics of Cocktail Representatives for Cytochrome P450 (CYP) 3A4, CYP2B6, CYP2C9, and CYP1A2 Substrates). Atabecestat (JNJ-54861911) is a potent oral and brain-penetrant BACE1 inhibitor [1] - The imbalance between production and clearance of amyloid β (Aβ) peptides and their accumulation in the brain is an early and crucial step in the pathogenesis of Alzheimer's disease (AD), and Atabecestat (JNJ-54861911) targets this process by inhibiting BACE1 to prevent de novo production of Aβ [2] - Two randomized, placebo-controlled, double-blind studies were conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of Atabecestat (JNJ-54861911) in young and elderly healthy participants, with regular blood samples and frequent CSF samples (up to 36 hours after the last dose) collected for analysis [1] - Investigational disease-modifying approaches for AD include reducing cerebral Aβ concentrations via BACE1 inhibition (e.g., Atabecestat (JNJ-54861911)) and clearing Aβ deposits via passive Aβ immunotherapy; combination of these two approaches may provide enhanced treatment efficacy and favorable safety [2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7218 mL | 13.6091 mL | 27.2183 mL | |
| 5 mM | 0.5444 mL | 2.7218 mL | 5.4437 mL | |
| 10 mM | 0.2722 mL | 1.3609 mL | 2.7218 mL |