 Chemical Structure.png)
Encequidar (formerly HM-30181; HM30181; HM30181A) is a novel, potent, selective, and orally bioavailable inhibitor of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter P-gp (P-glycoprotein). It was designed to improve the oral bioavailability of drugs that are P-gp substrates which may otherwise be pumped out of cells by P-gp, leading to drug resistance. Encequidar was supported by FDA in March 2021 for the new drug application for combination with oral paclitaxel in the treatment of patients with metastatic breast cancer. Oral paclitaxel and encequidar is the first world taxane to demonstrate superiority in radiologically confirmed tumor response rate, with reduced neuropathy and alopecia compared to IV paclitaxel in women with metastatic breast cancer. Encequidar showed the highest potency (IC(50)=0.63nM) among several MDR1 inhibitors, including cycloporin A, XR9576, and GF120918, and effectively blocked transepithelial transport of paclitaxel in MDCK monolayers (IC(50)=35.4nM). Encequidar is currently under clinical trials.
Physicochemical Properties
| Molecular Formula | C38H36N6O7 |
| Molecular Weight | 688.7284 |
| Exact Mass | 688.264 |
| CAS # | 849675-66-7 |
| Related CAS # | Encequidar mesylate;849675-87-2;Encequidar mesylate hydrochloride;2097125-58-9 |
| PubChem CID | 11399764 |
| Appearance | Light yellow to yellow solid powder |
| Density | 1.4±0.1 g/cm3 |
| Index of Refraction | 1.663 |
| LogP | 7.14 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 11 |
| Rotatable Bond Count | 11 |
| Heavy Atom Count | 51 |
| Complexity | 1220 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | AHJUHHDDCJQACA-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C38H36N6O7/c1-47-32-17-24-14-16-43(22-25(24)18-33(32)48-2)15-13-23-9-11-26(12-10-23)44-41-37(40-42-44)28-19-34(49-3)35(50-4)20-29(28)39-38(46)36-21-30(45)27-7-5-6-8-31(27)51-36/h5-12,17-21H,13-16,22H2,1-4H3,(H,39,46) |
| Chemical Name | N-(2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl)-4-oxo-4H-chromene-2-carboxamide |
| Synonyms | HM30181A HM30181 HM-30181A HM-30181 HM 30181A HM-30181 free base HM 30181. |
| 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 | When it comes to preventing rhodamine 123 efflux from CCRF-CEM T cells, encequidar (HM30181; HM30181A) is about equal to the standard Pgp inhibitor tariquidar (IC50, tariquidar: 8.2±2.0 nM, encequidar (HM30181): 13.1±2.3 nM) [1]. Compared to tariquitar, another third-generation P-gp inhibitor, encequidar (HM30181) is 20–50 times more powerful and shows strong selectivity for mP-gp [2]. |
| ln Vivo | Pgp substrate (R)-based PET scans [11C]NSC 657799 did not demonstrate (R)- [11C].When NSC was applied to mice treated with a vehicle, brain uptake was dramatically boosted by 657799 [1]. P-gp is mostly inhibited in intestinal endothelium cells by encequidar (HM30181), which may be advantageous because P-gp inhibition across the board, especially in the brain, may result in harmful side effects. In rats, encequidar (HM30181) enhanced co-administered NSC 125973's oral bioavailability by a factor of more than 12 [2]. |
| References |
[1]. Interaction of HM30181 with P-glycoprotein at the murine blood-brain barrier assessed with positron emission tomography. Eur J Pharmacol. 2012 Dec 5;696(1-3):18-27. [2]. Effects of HM30181, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers. Br J Clin Pharmacol. 2014 Sep;78(3):556-64. |
| Additional Infomation |
Encequidar is an inhibitor of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter P-glycoprotein (P-gp), with adjuvant activity. Upon oral administration, encequidar selectively binds to and inhibits the multidrug resistance (MDR) efflux pump P-gp, which prevents the efflux of various chemotherapeutic agents from intestinal epithelial cells to the gastrointestinal tract. This leads to an increase in both oral bioavailability and therapeutic efficacy. P-gp prevents the intestinal uptake and intracellular accumulation of various cytotoxic agents. Encequidar is not systemically absorbed. See also: Encequidar Mesylate (annotation moved to). Drug Indication Treatment of breast cancer , Treatment of soft tissue sarcoma |
Solubility Data
| Solubility (In Vitro) | DMSO : ~2.4 mg/mL (~3.48 mM) |
| 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 | 1.4519 mL | 7.2597 mL | 14.5195 mL | |
| 5 mM | 0.2904 mL | 1.4519 mL | 2.9039 mL | |
| 10 mM | 0.1452 mL | 0.7260 mL | 1.4519 mL |