MK-5046 (MK5046) is a novel and potent Bombesin receptor subtype-3 (BRS-3) agonist with anti-obesity effect. It has a strong affinity (mouse Ki = 1.6 nM, human Ki = 25 nM) for BRS-3. An orphan G protein-coupled receptor involved in the control of energy homeostasis is called bombesin receptor subtype-3 (BRS-3). Single oral doses of MK-5046 increased the metabolic rate during fasting and inhibited food intake for two hours and overnight in wild-type mice, but not in Brs3 knockout mice. MK-5046, administered at a dose of 25 mg kg(-1) · day(-1) for 14 days, caused a 9% reduction in body weight in diet-induced obese mice when compared to vehicle-dosed controls. 50% brain receptor occupancy was attained in mice at 0.34 ± 0.23 μM for plasma concentration. Effects on metabolic rate, as opposed to food intake, appear to be the main mechanism through which MK-5046 reduces weight when used chronically. In rats, the substance also caused slight increases in blood pressure, heart rate, and body temperature in addition to effectively lowering body weight. These subsequent effects on blood pressure, heart rate, and temperature were only momentary and became less pronounced with continued dosage. The first BRS-3 agonist with features appropriate for usage in larger mammals is MK-5046. Treatment with MK-5046 resulted in statistically significant and long-lasting weight loss in dogs. Initially, there were increases in body temperature and heart rate, but these decreased as the dosage was continued. Our findings support BRS-3 agonism as a novel strategy for treating obesity and show that MK-5046 has antiobesity efficacy in both rats and dogs.
Physicochemical Properties
| Molecular Formula | C20H18F6N4O |
| Molecular Weight | 444.37 |
| Exact Mass | 444.138 |
| Elemental Analysis | C, 54.06; H, 4.08; F, 25.65; N, 12.61; O, 3.60 |
| CAS # | 1022152-70-0 |
| Related CAS # | (R)-MK-5046; 1021736-25-3 |
| PubChem CID | 49871766 |
| Appearance | White to light yellow solid powder |
| LogP | 4.473 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 31 |
| Complexity | 632 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | O[C@](CC1=NC(CC2(C(F)(F)F)CC2)=CN1)(C(F)(F)F)C3=CC=C(N4C=CC=N4)C=C3 |
| InChi Key | UJINBEQCDMOAHM-SFHVURJKSA-N |
| InChi Code | InChI=1S/C20H18F6N4O/c21-19(22,23)17(6-7-17)10-14-12-27-16(29-14)11-18(31,20(24,25)26)13-2-4-15(5-3-13)30-9-1-8-28-30/h1-5,8-9,12,31H,6-7,10-11H2,(H,27,29)/t18-/m0/s1 |
| Chemical Name | (2S)-1,1,1-trifluoro-2-(4-pyrazol-1-ylphenyl)-3-[5-[[1-(trifluoromethyl)cyclopropyl]methyl]-1H-imidazol-2-yl]propan-2-ol |
| Synonyms | MK-5046; MK5046; MK 5046 |
| 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) |
Biological Activity
| Targets | human BRS3 ( IC50 = 28 nM ); mouse BRS3 ( IC50 = 5.4 nM ); rat BRS3 ( IC50 = 1.2 nM ); dog BRS3 ( IC50 = 6.5 nM ); rhesus BRS3 ( IC50 = 50 nM ) |
| ln Vitro | The IC50 values of MK-5046 against human, mouse, mouse, dog and macaque BRS3 are 28, 5.4, 1.2, 6.5 and 50 nM respectively [2]. The Ki values of MK-5046 for human, mouse, rat, dog and macaque BRS3 are 3.4, 1.6, 0.6, 9.9 and 2.4 nM respectively[2]. The EC50 values of MK-5046 against human, mouse, monkey, dog and macaque BRS3 are 14, 21, 2.2, 1.6 and 6.9 respectively. MK-5046 inhibits the rabbit calcium channel diltiazem (DLZ) site with an IC50 value of 1.9 μM[2]. |
| ln Vivo | MK-5046 (3, 10 and 30 mg/kg; pathway, once) inhibits channel opening and increases resting metabolic rate (MR) in response to diet-induced response (DIO) and diet [1]. 5, 25 and 50 mg/kg; subcutaneous injection once daily for 14 days) significantly reduced body weight and food intake in DIO mice [1]. Animal model: Male C57BL/6N mice, high-fat diet is the diet-induced obesity (DIO) model [1] Dosage: 3, 10 and 30 mg/kg Dosing method: Orally; 3, 10 and 30 mg/kg, once Results: DIO mice dose-dependently suppressed food intake at 2 hours and overnight. But it had no effect on Brs3 knockout mice. |
| Animal Protocol |
Male C57BL/6N mice with high-fat diet for the diet-induced obese (DIO) model 3, 10 and 30 mg/kg Oral administration; 3, 10 and 30 mg/kg for once |
| References |
[1]. Antiobesity effect of MK-5046, a novel bombesin receptor subtype-3 agonist. J Pharmacol Exp Ther. 2011 Feb;336(2):356-364. [2]. Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity. ACS Med Chem Lett. 2010 Oct 18;2(1):43-47. [3]. The Nonpeptide Agonist MK-5046 Functions As an Allosteric Agonist for the Bombesin Receptor Subtype-3. J Pharmacol Exp Ther. 2022 Aug;382(2):66-78. |
Solubility Data
| Solubility (In Vitro) | DMSO: ~14.3 mg/mL (~32.2 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.43 mg/mL (3.22 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 14.3 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: ≥ 1.43 mg/mL (3.22 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 14.3 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: ≥ 1.43 mg/mL (3.22 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 14.3 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 | 2.2504 mL | 11.2519 mL | 22.5038 mL | |
| 5 mM | 0.4501 mL | 2.2504 mL | 4.5008 mL | |
| 10 mM | 0.2250 mL | 1.1252 mL | 2.2504 mL |