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Verubecestat TFA (also known as MK-8931; SCH-900931), the trifluoroacetic acid salt form of MK-8931, is a beta-secretase 1 and BACE1 inhibitor with anti-AD (Alzheimer's disease) activity. It is in Phase 3 clinical trial for treatment of Alzheimer's disease. Amyloidogenic pathway in Alzheimer's disease (AD) involves breakdown of APP by β-secretase followed by γ-secretase and results in formation of amyloid beta plaque. β-secretase has been a promising target for developing novel anti-Alzheimer drugs.MK-8931 binds significantly to β-secretase. target: BACE1. In vitro:MK-8931 can effectively reduce Aβ40 in cells with a Ki of 7.8 nM and an IC50 of 13 nM. Docking revealed that, with respect to their free binding energy, acylguanidine 7a has the lowest binding energy followed by MK-8931 and pioglitazone and binds significantly to β-secretase.
| ln Vitro |
An inhibitor of beta-site amyloid precursor protein cleaving enzyme 1/2 (BACE1/2) is called verubecestat TFA (MK-8931). Verubecestat TFA is unlikely to be an inhibitor of CYP-mediated drug-drug interactions because it does not significantly inhibit human CYP isoforms 1A2, 2C9, 2C19, 2D6, and 3A4 (IC50 >40 μM) [1]. Verubecestat TFA's IC50 values in HEK293 APPSwe/Lon cells for Aβ1-40, Aβ1-42, and sAPPβ are 2.1 nM, 0.7 nM, and 4.4 nM, respectively[1].
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| ln Vivo |
In Sprague-Dawley (SD) rats, verubecestat TFA (MK-8931; 3 mg/kg; IV or PO) has a T1/2 of 1.9 hours, a CL of 46 mL/min/kg, and a Vss of 5.4 L. AUC is 1.1 μM·h, C max is 0.27 μM, and /kg[1]. In cynomolgus monkeys, verubecestat TFA (1 mg/kg; IV) has a T1/2 of 4.9 hours, a CL of 21 mL/min/kg, and a Vss of 7.5 L/kg [1]. In beagle dogs, the T1/2 for verubecestat TFA (1 mg/kg; IV) is 9.7 hours, the CL is 4.3 mL/min/kg, and the Vss is 2.7 L/kg [1]. Rats treated with verubecestat TFA (30 mg/kg; PO; BID, 5 days) exhibit a moderate (1.4-fold) increase in CYP 3A1 activity, but CYP 1A1, 1A2, 2B, 3A2, and 4A expression remain largely unchanged[1]. Verubecestat TFA decreases CSF and cortical Aβ40 in a dose-dependent manner; its ED50 values are 5 and 8 mg/kg, respectively, and its EC50 values are 48 and 81 nM, respectively, for unbound plasma CSF and cortical Aβ40 [1]. The oral doses of verubecestat TFA (3 and 10 mg/kg) resulted in a significant decrease in CSF Aβ40 levels. The effect of the drug peaked 12 hours after dosing, with 72% and 81% reduction in CSF Aβ, respectively. %)[1].
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| References |
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| Molecular Formula |
C19H18F5N5O5
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| Molecular Weight |
523.43
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| Exact Mass |
523.094
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| Elemental Analysis |
C, 43.60; H, 3.47; F, 18.15; N, 13.38; O, 15.28; S, 6.12
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| CAS # |
2095432-65-6
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| Related CAS # |
Verubecestat;1286770-55-5
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| PubChem CID |
129896720
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
35
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| Complexity |
827
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| Defined Atom Stereocenter Count |
1
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| SMILES |
S1(C[C@@](C)(C2C(=CC=C(C=2)NC(C2C=CC(=CN=2)F)=O)F)N=C(N)N1C)(=O)=O.FC(C(=O)O)(F)F
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| InChi Key |
MNYVOIVLGITLBF-LMOVPXPDSA-N
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| InChi Code |
InChI=1S/C17H17F2N5O3S.C2HF3O2/c1-17(9-28(26,27)24(2)16(20)23-17)12-7-11(4-5-13(12)19)22-15(25)14-6-3-10(18)8-21-14;3-2(4,5)1(6)7/h3-8H,9H2,1-2H3,(H2,20,23)(H,22,25);(H,6,7)/t17-;/m0./s1
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| Chemical Name |
N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide;2,2,2-trifluoroacetic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| 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)
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| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9105 mL | 9.5524 mL | 19.1048 mL | |
| 5 mM | 0.3821 mL | 1.9105 mL | 3.8210 mL | |
| 10 mM | 0.1910 mL | 0.9552 mL | 1.9105 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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