[CAS NO. 1286770-55-5] Verubecestat
PRODUCTS SPECIFICATIONS [1286770-55-5]
DESCRIPTION [1286770-55-5]
Overview
| MDL | MFCD28963974 |
|---|---|
| Molecular Weight | 409.41 |
| Molecular Formula | C17H17F2N5O3S |
| 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 |
1 Publications Citing Use of MCE
Summary
IC50 & Target
Ki: 2.2 nM (BACE1) and 0.38 nM (BACE2) [1]
In Vitro
Verubecestat (MK-8931) is a β-site amyloid precursor protein cleaving enzyme 1/2 (BACE1/2) inhibitor. Verubecestat does not significantly inhibit human CYP isoforms 1A2, 2C9, 2C19, 2D6, and 3A4 (all IC
50
>40 μM), indicating that the compound is unlikely to be a perpetrator of CYP-mediated drug-drug interactions
[1]
.
Verubecestat has IC
50
s of 2.1 nM, 0.7 nM, 4.4 nM for Aβ1-40, Aβ1-42, sAPPβ in HEK293 APP
Swe/Lon
cells
[1]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
Verubecestat (MK-8931; 3 mg/kg; IV or oral) has a T
1/2
of 1.9 hours, a CL of 46 mL/min/kg, a V
ss
of 5.4 L/kg, a C
max
of 0.27 μM and a AUC of 1.1 μM•h for Sprague-Dawley (SD) rats
[1]
.
Verubecestat (1 mg/kg; IV) has a T
1/2
of 4.9 hours, a CL of 21 mL/min/kg, a V
ss
of 7.5 L/kg for cynomolgus monkeys
[1]
.
Verubecestat (1 mg/kg; IV) has a T
1/2
of 9.7 hours, a CL of 4.3 mL/min/kg, a V
ss
of 2.7 L/kg for beagle dogs
[1]
.
Verubecestat (30 mg/kg; orally; BID for 5 days) causes a modest (1.4-fold) induction of CYP 3A1 activity but does not significantly alter the expression of CYPs 1A1, 1A2, 2B, 3A2, or 4A in rats
[1]
.
Verubecestat dose-dependently reduces CSF and cortex Aβ40 with ED
50
values of 5 and 8 mg/kg, respectively, corresponding to unbound plasma EC
50
values of 48 and 81 nM, respectively
[1]
.
Verubecestat (3 and 10 mg/kg; orally) reduces profound, sustained of CSF Aβ40 levels and has peak effects on CSF Aβ lowering (72 and 81% reduction at 3 and 10 mg/kg, respectively) 12 h after dosing
[1]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: | Sprague-Dawley (SD) rats [1] |
| Dosage: | 3 mg/kg (Pharmacokinetic Analysis) |
| Administration: | IV or oral |
| Result: | Had a T 1/2 of 1.9 hours, a CL of 46 mL/min/kg, a V ss of 5.4 L/kg, a C max of 0.27 μM and a AUC of 1.1 μM•h. |
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT01537757 | Merck Sharp & Dohme LLC |
Alzheimer´s Disease
|
March 2012 | Phase 1 |
| NCT01953601 | Merck Sharp & Dohme LLC |
Amnestic Mild Cognitive Impairment|Alzheimer´s Disease|Prodromal Alzheimer´s Disease
|
November 5, 2013 | Phase 3 |
| NCT01496170 | Merck Sharp & Dohme LLC |
Alzheimer´s Disease
|
December 2011 | Phase 1 |
| NCT02910739 | Merck Sharp & Dohme LLC |
Amnestic Mild Cognitive Impairment|Alzheimer´s Disease|Prodromal Alzheimer´s Disease
|
October 11, 2016 | Phase 1 |
| NCT01739348 | Merck Sharp & Dohme LLC |
Alzheimer´s Disease
|
November 30, 2012 | Phase 2|Phase 3 |
Appearance
Solid
Shipping
Room temperature in continental US; may vary elsewhere.
Storage
| Powder | -20°C | 3 years |
|---|---|---|
| 4°C | 2 years | |
| In solvent | -80°C | 6 months |
| -20°C | 1 month |
Solvent & Solubility
DMSO : ≥ 35 mg/mL ( 85.49 mM )
* "≥" means soluble, but saturation unknown.
Stock Solutions
| Concentration Solvent Mass | 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 |
References
- [1] Scott JD, et al. Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer'sDisease. Med Chem. 2016 Dec 8;59(23):10435-10450.
- [2] Yan R, et al. Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Transl Neurodegener. 2016 Jul 14;5:13.
Synonyms
