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Purity: ≥98%
Verubecestat (formerly known as MK8931; SCH-900931) is a beta-secretase 1 and BACE1 inhibitor that 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 (MK-8931). Since verubecestat does not significantly inhibit human CYP isoforms 1A2, 2C9, 2C19, 2D6, and 3A4 (IC50 >40 μM), it is unlikely that the substance will inhibit drug-drug interactions mediated by CYP [1]. Verubecestat's IC50 values in HEK293 APPSwe/Lon cells are 2.1 nM, 0.7 nM, and 4.4 nM for Aβ1-40, Aβ1-42, and sAPPβ, respectively [1].
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| ln Vivo |
With a T1/2 of 1.9 hours, a CL of 46 mL/min/kg, and a Vss of Sprague-Dawley (SD) rats [1], verubecestat (MK-8931; 3 mg/kg; IV or PO) has a C max of 5.4 L/kg, a C max of 0.27 μM, and an AUC of 1.1 μM·h. In cynomolgus monkeys, verubecestat (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 (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 (30 mg/kg; oral; BID, 5 days) exhibit a moderate (1.4-fold) increase in CYP 3A1 activity, but CYP 1A1, 1A2, 2B, 3A2, and 4A expression are not significantly changed [1]. Verubecestat 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]. Verubecestat, taken orally at doses of 3 and 10 mg/kg, significantly decreased CSF Aβ40 levels. The drug's effect on CSF Aβ reduction peaked 12 hours after dosing, at 72% and 81%, respectively, at these dosages[1].
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| Animal Protocol |
Animal/Disease Models: SD (Sprague-Dawley) rats[1]
Doses: 3 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: IV or oral Experimental Results: Had a T1/2 of 1.9 hrs (hours), a CL of 46 mL/min/kg, a Vss of 5.4 L/kg, a Cmax of 0.27 μM and a AUC of 1.1 μM·h. |
| References |
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| Additional Infomation |
Verubecestat is under investigation for the treatment of Alzheimer's Disease, Prodromal Alzheimer's disease, and Amnestic Mild Cognitive Impairment. Verubecestat is Merck’s investigational oral β-site amyloid precursor protein cleaving enzyme (BACE1 or β secretase) inhibitor. In July 2013, Merck announced positive results for Phase Ib trials of Verubecestat. In the study, administration of Verubecestat at doses of 12, 40 and 60 mg resulted in a dose-dependent and sustained reduction in the levels of Ab40, a measure of BACE1 activity, in CSF from baseline of 57, 79 and 84 percent, respectively.
Mechanism of Action The amyloid hypothesis asserts that the formation of amyloid peptides that lead to amyloid plaque deposits in the brain is a primary contributor to the underlying cause of Alzheimer's disease. BACE is believed to be a key enzyme in the production of amyloid β peptide. Evidence suggests that inhibiting BACE decreases the production of amyloid β peptide and may therefore reduce amyloid plaque formation and modify disease progression. |
| Molecular Formula |
C17H17F2N5O3S
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|---|---|---|
| Molecular Weight |
409.41
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| Exact Mass |
409.102
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| Elemental Analysis |
C, 49.87; H, 4.19; F, 9.28; N, 17.11; O, 11.72; S, 7.83
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| CAS # |
1286770-55-5
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| Related CAS # |
Verubecestat TFA;2095432-65-6
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| PubChem CID |
51352361
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.655
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| LogP |
-0.56
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
28
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| Complexity |
744
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C(C1=NC=C(F)C=C1)NC2=CC=C(F)C([C@@](C3)(C)N=C(N)N(C)S3(=O)=O)=C2
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| InChi Key |
YHYKUSGACIYRML-KRWDZBQOSA-N
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| InChi Code |
InChI=1S/C17H17F2N5O3S/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/h3-8H,9H2,1-2H3,(H2,20,23)(H,22,25)/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
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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) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.11 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4425 mL | 12.2127 mL | 24.4254 mL | |
| 5 mM | 0.4885 mL | 2.4425 mL | 4.8851 mL | |
| 10 mM | 0.2443 mL | 1.2213 mL | 2.4425 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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