MK-1064

Alias: MK-1064; MK1064; MK 1064

Cat No.:V2874 Purity: ≥98%

COA Product Data Instructions for use SDS

MK-1064 (MK1064) is a novel, potent, selective and orally bioavailable antagonist of Orexin OX2 Receptor (OX2R), with the potential to be used for the treatment of insomnia.

MK-1064 Chemical Structure CAS No.: 1207253-08-4
Product category: OX Receptor

This product is for research use only, not for human use. We do not sell to patients.

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Top Publications Citing lnvivochem Products

Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

Science Adv 2022: 8, eabm9427.

Nature 597, 119–125 (2021)

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J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

PNAS Nexus 2022,1(3):pgac063.

ACS Nano 2023,17(10):9110-9125.

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Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Clinical Trial Information
Biological Data

Product Description

MK-1064 (MK1064) is a novel, potent, selective and orally bioavailable antagonist of Orexin OX2 Receptor (OX2R), with the potential to be used for the treatment of insomnia. Orexin receptors (OX1R, OX2R) are the primary mediators of arousal promotion, and they are used by orexin neuropeptides to control sleep/wake cycles. An antagonist of OX2R singlet is MK-1064. MK-1064 has been shown in preclinical settings to enhance sleep in rats by increasing both REM and NREM sleep at OX2R occupancies higher than those seen with dual orexin receptor antagonists. Like dual antagonists, MK-1064 helps dogs sleep longer in both NREM and REM phases without making them cataplexy. MK-1064 demonstrated dose-dependent increases in subjective somnolence (via Karolinska Sleepiness Scale and Visual Analogue Scale measures) and sleep (via polysomnography), including increased REM and NREM sleep.

Biological Activity I Assay Protocols (From Reference)

Targets

OX₁ ( IC50 = 1789 nM ); OX₂ ( IC50 = 18 nM ); OX₁ ( Ki = 1584 nM ); OX₂ ( Ki = 0.5 nM )

ln Vitro

In vitro activity: MK-1064 is an innovative, strong, specific, and orally bioavailable antagonist of the Orexin OX2 Receptor that may be used to treat sleeplessness. Through orexin receptors (OX1R, OX2R), orexin neuropeptides control sleep and wakefulness; OX2R is the main mediator of arousal promotion. MK-1064 is an antagonist of OX2R single. Preclinically, MK-1064 increases sleep in rats at OX2R occupancies higher than those seen for dual orexin receptor antagonists. It also increases both REM and NREM sleep.

ln Vivo

MK-1064 (30 mg/kg, oral administration) electively induces sleep via OX2R in wild-type mice in rodents[2].
MK-1064 (30 mg/kg, oral administration, 5 days) reverses the struggle behavior that rats pretreated with CNO had developed[3].
MK-1064 (1-5 mg/kg, intravenous injection/oral administration) exhibits moderate oral bioavailability and clearance in rat, dog, and rhesus monkey[1].

Animal Protocol

Wild-type and OX₂R knockout mice
30 mg/kg
Oral administration

References

[1]. Discovery of 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064): a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia. ChemMedChem. 2014 Feb;9(2):311-22.

[2]. Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man. Sci Rep. 2016 Jun 3;6:27147.

[3]. Orexin 2 receptor regulation of the hypothalamic-pituitary-adrenal (HPA) response to acute and repeated stress. Neuroscience. 2017 Apr 21;348:313-323.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula

C24H20CLN5O3

Molecular Weight

461.91

Exact Mass

461.13

Elemental Analysis

C, 62.41; H, 4.36; Cl, 7.67; N, 15.16; O, 10.39

CAS #

1207253-08-4

Related CAS #

1207253-08-4

Appearance

Solid powder

SMILES

COC1=C(N=C(C=C1)CNC(=O)C2=C(N=CC(=C2)C3=CC(=CN=C3)Cl)C4=CC=CC=N4)OC

InChi Key

CKTWQGHVNRYNCM-UHFFFAOYSA-N

InChi Code

InChI=1S/C24H20ClN5O3/c1-32-21-7-6-18(30-24(21)33-2)14-29-23(31)19-10-16(15-9-17(25)13-26-11-15)12-28-22(19)20-5-3-4-8-27-20/h3-13H,14H2,1-2H3,(H,29,31)

Chemical Name

5-(5-chloropyridin-3-yl)-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2-pyridin-2-ylpyridine-3-carboxamide

Synonyms

MK-1064; MK1064; MK 1064

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)

Solubility Data

Solubility (In Vitro)

DMSO: 50~98 mg/mL (108.3~199.2 mM)

Water: N/A

Ethanol: N/A

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.41 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.1649 mL	10.8246 mL	21.6492 mL
	5 mM	0.4330 mL	2.1649 mL	4.3298 mL
	10 mM	0.2165 mL	1.0825 mL	2.1649 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.

Calculator

Mass

Concentration

Volume

Molecular Weight*

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Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

Calculate the Mass of a compound required to prepare a solution of known volume and concentration
Calculate the Volume of solution required to dissolve a compound of known mass to a desired concentration
Calculate the Concentration of a solution resulting from a known mass of compound in a specific volume

See Example

An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
Enter 10 in the Concentration box and choose the correct unit (mM)
Enter 5 in the Volume box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Concentration (Start)

Volume (Start)

Concentration (End)

Volume (End)

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
Enter 25 into the Concentration (End) box and select the correct unit (mM)
Enter 25 into the Volume (End) box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

Total molecular weight

g/mol

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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:

To calculate molar mass of a chemical compound, please enter the chemical/molecular formula and click the “Calculate’ button.

Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

Volume (to add to vial)

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Desired Reconstitution Concentration

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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
Click the “Calculate” button
The answer appears in the Volume (to add to vial) box

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

Dosage mg/kg

Average weight of animals g

Dosing volume per animal μL

Number of animals

Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

% DMSO

% Tween 80

% ddH₂O

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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.

Note： (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.

Clinical Trial Information

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT02549014	Completed	Drug: MK-1064 Drug: Placebo	Pharmacokinetics	Merck Sharp & Dohme LLC	July 6, 2009	Phase 1
NCT02549027	Completed	Drug: MK-1064 Drug: Placebo Drug: MK-6096	Polysomnography	Merck Sharp & Dohme LLC	November 6, 2009	Phase 1

Biological Data

MK-1064 dose-dependently promotes somnolence and attenuates arousal in healthy human subjects.Sci Rep.2016 Jun 3;6:27147.
MK-1064 promotes sleep in healthy subjects.Sci Rep.2016 Jun 3;6:27147.
Sleep effects of MK-1064 30 mg/kg are OX2R-dependent.
Enrolment information for Phase I studies in healthy human volunteers.Sci Rep.2016 Jun 3;6:27147.
MK-1064 dose-dependently promotes both NREM and REM sleep during the active phase in rats.Sci Rep.2016 Jun 3;6:27147.
MK-1064 requires higher OX2R occupancies to promote sleep relative to DORA-12 in rats.Sci Rep.2016 Jun 3;6:27147.
MK-1064 effectively promotes somnolence but not cataplexy in canines.Sci Rep.2016 Jun 3;6:27147.