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Filorexant (formerly known as MK-6096) is a novel, orally bioavailable, potent and selective reversible antagonist of OX(1)R and OX(2)R currently in clinical development for insomnia. In radioligand binding and functional cell based assays, MK-6096 demonstrated potent binding and antagonism of both human OX(1)R and OX(2)R. MK-6096 significantly increased sleep in dogs (0.25 and 0.5 mg/kg) and rats (3-30 mg/kg) and occupies 90% of human OX(2)Rs expressed in transgenic rats at a plasma concentration of 142 nM. It also significantly reduced locomotor activity. MK-6096 is a new and targeted medication for the management of sleeplessness.
Physicochemical Properties
| Molecular Formula | C24H25FN4O2 | |
| Molecular Weight | 420.49 | |
| Exact Mass | 420.196 | |
| Elemental Analysis | C, 68.55; H, 5.99; F, 4.52; N, 13.32; O, 7.61 | |
| CAS # | 1088991-73-4 | |
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| PubChem CID | 25128145 | |
| Appearance | Off-white to yellow solid powder | |
| Density | 1.2±0.1 g/cm3 | |
| Boiling Point | 540.2±50.0 °C at 760 mmHg | |
| Flash Point | 280.5±30.1 °C | |
| Vapour Pressure | 0.0±1.4 mmHg at 25°C | |
| Index of Refraction | 1.576 | |
| LogP | 2.77 | |
| Hydrogen Bond Donor Count | 0 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 5 | |
| Heavy Atom Count | 31 | |
| Complexity | 588 | |
| Defined Atom Stereocenter Count | 2 | |
| SMILES | FC1=C([H])N=C(C([H])=C1[H])OC([H])([H])[C@@]1([H])C([H])([H])N(C(C2C([H])=C(C([H])([H])[H])C([H])=C([H])C=2C2N=C([H])C([H])=C([H])N=2)=O)[C@]([H])(C([H])([H])[H])C([H])([H])C1([H])[H] |
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| InChi Key | NPFDWHQSDBWQLH-QZTJIDSGSA-N | |
| InChi Code | InChI=1S/C24H25FN4O2/c1-16-4-8-20(23-26-10-3-11-27-23)21(12-16)24(30)29-14-18(6-5-17(29)2)15-31-22-9-7-19(25)13-28-22/h3-4,7-13,17-18H,5-6,14-15H2,1-2H3/t17-,18-/m1/s1 | |
| Chemical Name | [(2R,5R)-5-[(5-fluoropyridin-2-yl)oxymethyl]-2-methylpiperidin-1-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone | |
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| 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 |
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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) |
Biological Activity
| Targets | Orexin receptor ( Ki < 3 nM ) |
| ln Vitro | Filorexant (MK-6096) exhibited strong binding and antagonistic effects on human OX(1)R and OX(2)R in radioligand binding and functional cell-based assays (<3 nM for binding and 11 nM for FLIPR), without causing any notable side effects on a panel of more than 170 receptors and enzymes. Filorexant (MK-6096) occupies 90% of human OX(2)Rs expressed in transgenic rats at a plasma concentration of 142 nM. |
| ln Vivo | Filorexant (MK-6096) significantly increased sleep and decreased locomotor activity in a dose-dependent manner in rats (3-30 mg/kg) and dogs (0.25 and 0.5 mg/kg). |
| Animal Protocol | The male Sprague Dawley rats (n = 8/study; age: 3-6 months; weight: 450-600 g) were kept in separate housing, given free access to food and water, and kept in a 12 h light/12 h dark cycle, with lights coming on at 4:00 and going off at 16:00. Utilizing a counterbalanced crossover design, sleep studies were performed to assess Filorexant (3 and 10 mg/kg, p.o.), DORA-22 (10 mg/kg, p.o.), and almorexant (3 and 30 mg/kg, p.o.). For DORA-22 and Filorexant, respectively, all animals were alternately treated with drug and vehicle daily for either 3 or 7 consecutive days: 2 baseline days (no dosing), a 2 day vehicle-only run-in, a 3 or 7-day arm of drug or vehicle, and a 3 or 7-day conditional crossover. The effects of compound treatments were assessed after administration in the active phase in comparison to the vehicle (20% Vitamin E TPGS, p.o.). |
| References |
[1]. Pharmacological characterization of MK-6096 - a dual orexin receptor antagonist for insomnia. Neuropharmacology. 2012 Feb;62(2):978-87. [2]. Discovery of [(2R,5R)-5-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): a dual orexin receptor antagonist with potent sleep-promoting properties. ChemMedChem. 2012 Mar 5;7(3):415-24, 337. |
| Additional Infomation | Filorexant has been used in trials studying the prevention and treatment of Migraine, Headache, Polysomnography, Diabetic Neuropathy, Painful, and Major Depressive Disorder, Recurrent. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.95 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 (5.95 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3782 mL | 11.8909 mL | 23.7818 mL | |
| 5 mM | 0.4756 mL | 2.3782 mL | 4.7564 mL | |
| 10 mM | 0.2378 mL | 1.1891 mL | 2.3782 mL |