Atabecestat HCl (formerly known as JNJ-54861911 HCl), the hydrochloride salt of Atabecestat, is a novel potent, oral, and brain-penetrant inhibitor of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which is an enzyme that is 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;
Appearance	White to off-white solid powder
Density	1.4±0.1 g/cm3
Index of Refraction	1.681
LogP	1.63
SMILES	S1C(N)=N[C@](C=C1)(C)C1C(=CC=C(C=1)NC(C1C=CC(C#N)=CN=1)=O)F
Chemical Name	(S)-N-(3-(2-amino-4-methyl-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide hydrochloride
Synonyms	JNJ-54861911 HCl; RSC-385896 HCl;JNJ54861911 HCl; RSC 385896;JNJ 54861911; RSC385896 hydrochloride; JNJ-54861911-AAA;AtabecestatHCl
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
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

ln Vitro	In vitro activity: Atabecestat (formerly known as JNJ-54861911) is a novel potent, oral, and brain-penetrant inhibitor of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which is an enzyme that is up-regulated in Alzheimer’s disease. β-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimers 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. Kinase Assay: JNJ-54861911 inhibited BACE1 with IC50 of 2,600 nM to 1 nM.
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].
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.
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.

Solubility Data

Solubility (In Vitro)

DMSO: 10 mM Water:< 1 mg/mL Ethanol:< 1 mg/mL

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

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.