Suvorexant (MK-4305)

Catalog No.S7279

Suvorexant (MK-4305) is a potent dual OX receptor antagonist with Ki of 0.55 nM and 0.35 nM for OX1 receptor and OX2 receptor, respectively. Phase 3.

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Suvorexant (MK-4305) Chemical Structure

Suvorexant (MK-4305) Chemical Structure
Molecular Weight: 450.92

Validation & Quality Control

Quality Control & MSDS

Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description Suvorexant (MK-4305) is a potent dual OX receptor antagonist with Ki of 0.55 nM and 0.35 nM for OX1 receptor and OX2 receptor, respectively. Phase 3.
Targets OX2 receptor [1] OX1 receptor [1]
IC50 0.35 nM(Ki) 0.55 nM(Ki)
In vitro
In vivo Suvorexant has excellent passive permeability and oral bioavailability, and induces favorable sleep effects in rats. [1] In addition, suvorexant significantly and dose-dependently reduces locomotor activity and promotes sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). [2]
Features Dual OX antagonist currently in Phase III clinical trials for the modulation of sleep.

Protocol(Only for Reference)

Kinase Assay: [1]

FLIPR Assay For intracellular calcium measurements, Chinese hamster ovary (CHO) cells expressing the Ile408-Val variant of the orexin 1 receptor or the human orexin 2 receptor, are grown in Iscove’s modified DMEM containing 2 mM l-glutamine, 0.5 g/mL G418, 1% hypoxanthine-thymidine supplement, 100 U/mL penicillin, 100 ug/mL streptomycin, and 10% heat-inactivated fetal calf serum. The cells are seeded at 20000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-d-lysine. All reagents are from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37 °C and 6% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 0.5 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES and 2.5 mM probenecid, pH 7.4) for use in the assay at a final concentration of 0.3−2 nM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted and pipetted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed three times with 100 μL assay buffer and then incubated for 60 min (37 °C, 6% CO2) in 60 μL of assay buffer containing 1 μM Fluo-4AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells washed three times with 100 μL of assay buffer. Then 30 μL of that same buffer is left in each well. Within the fluorescent imaging plate reader, test compounds are added to the plate in a volume of 15 μL, incubated for 5 min, and finally 15 μL of agonist is added. Fluorescence is measured for each well at 1 s intervals for 1 min and at 6 s intervals for 4 min, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 0.3−2 nM Ala-6,12 orexin-A with buffer in place of antagonist. For each antagonist, the IC50 value (the concentration of compound needed to inhibit 50% of the agonist response) is determined.

Animal Study: [1]

Animal Models Adult male Sprague−Dawley rats
Formulation 20% aqueous solution of TPGS
Dosages ~10 mg/kg
Administration Oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Cox CD, et al. J Med Chem. 2010, 53(14), 5320-5332.

[2] Mould R, et al. Br J Pharmacol. 2013, doi: 10.1111/bph.12245.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02849184 Not yet recruiting Hypertension|Insomnia Jichi Medical University|Merck Sharp & Dohme Corp.|Satt C  ...more Jichi Medical University|Merck Sharp & Dohme Corp.|Satt Co.,Ltd September 2016 Phase 4
NCT02849548 Not yet recruiting Posttraumatic Stress Disorder Howard University|Georgetown-Howard Universities Center f  ...more Howard University|Georgetown-Howard Universities Center for Clinical and Translational Science July 2016 Phase 4
NCT02750306 Recruiting Insomnia|Alzheimers Disease Merck Sharp & Dohme Corp. May 2016 Phase 3
NCT02704754 Recruiting Insomnia|Posttraumatic Stress Disorder Howard University|Merck Sharp & Dohme Corp. May 2016 Phase 4
NCT02785406 Recruiting Cocaine Use Disorder|Anxiety The University of Texas Health Science Center, Houston|Pe  ...more The University of Texas Health Science Center, Houston|Peter F. McManus Charitable Trust May 2016 Phase 2

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Chemical Information

Download Suvorexant (MK-4305) SDF
Molecular Weight (MW) 450.92
Formula

C23H23ClN6O2

CAS No. 1030377-33-3
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 10 mg/mL (22.17 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 4% DMSO+10% PEG 400+10% Tween 80 5 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 5-Chloro-2-[(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole

Tech Support

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