MK-7145 is a novel, potent, selective and orally bioactive ROMK inhibitor with IC50 of 0.045 μM and has the potential for the treatment of hypertension and heart failure. ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. MK-7145 is selective against other cardiac ion channels such as Cav1.2 and Nav1.5 (IC50 > 30 μM). MK-7145 was not a potent reversible inhibitor of human CYP3A4, CYP2C9, or CYP2D6 (IC50 > 50μM) and was not a time-dependent inhibitor of CYP3A4 at 10and 50 μM. MK-7145 caused dose-dependent lowering of blood pressure in a subchronic SHR model. MK-7145 is the first small molecule ROMK inhibitor to enter clinical development.
Physicochemical Properties
| Molecular Formula | C26H30N2O6 |
| Molecular Weight | 466.526 |
| Exact Mass | 466.21 |
| CAS # | 1255204-84-2 |
| Related CAS # | 1255204-84-2;1255204-85-3 (2HCl); |
| PubChem CID | 59568713 |
| Appearance | Typically exists as solid at room temperature |
| LogP | 1.904 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 34 |
| Complexity | 694 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | O[C@H](C1=C(C)C2=C(C(OC2)=O)C=C1)CN3CCN(C[C@@H](C4=C(C)C5=C(C(OC5)=O)C=C4)O)CC3 |
| InChi Key | OCKGFTQIICXDQW-ZEQRLZLVSA-N |
| InChi Code | InChI=1S/C26H30N2O6/c1-15-17(3-5-19-21(15)13-33-25(19)31)23(29)11-27-7-9-28(10-8-27)12-24(30)18-4-6-20-22(16(18)2)14-34-26(20)32/h3-6,23-24,29-30H,7-14H2,1-2H3/t23-,24-/m0/s1 |
| Chemical Name | 5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one) |
| Synonyms | MK-7145; MK 7145; MK7145. |
| 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
| ln Vitro | MK-7145 (compound 12) was evaluated against other Kir channel family members. Even at doses as high as 30 μM, it shows no discernible action on the Kir2.1, Kir2.3, Kir4.1, or Kir7.1 channels. Additionally, MK-7145 exhibits selectivity for additional cardiac ion channels, including Nav1.5 and Cav1.2 (IC50>30 μM). Using HEK293 cells that were transfected with human SERT, MK-7145 inhibited 3H-serotonin uptake with an IC50 value of 2.40±0.32 μM (n=5). This was based on an extensive counterscreen panel that included over 150 receptors, enzymes, and ion channels. Only three activities at <10 μM were shown by MK-7145: acetylcholinesterase, ACES, IC50=9.94 μM, growth inhibitory isoform 1, sst1, IC50=2.63 μM, and human serotonin transporter, SERT, IC50=0.12 μM. Because MK-7145 is a substrate of human Pgp (human Mdr1 BAAB ratio = 12), in addition to its greater ROMK potency and in vivo efficiency, it should offer a sizable safety window for SERT off-target activities. |
| References | [1]. Tang H, et al. Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure. ACS Med Chem Lett. 2016 May 12;7(7):697-701. |
| Additional Infomation | MK-7145 has been used in trials studying the treatment of Hypertension and Renal Insufficiency. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1435 mL | 10.7174 mL | 21.4348 mL | |
| 5 mM | 0.4287 mL | 2.1435 mL | 4.2870 mL | |
| 10 mM | 0.2143 mL | 1.0717 mL | 2.1435 mL |