Encequidar mesylate (HM30181; HM-30181A; Oraxol), the mesylate salt of encequidar, is a novel, highly specific, and orally bioavailable inhibitor of P-glycoprotein (P-gp), which is an adenosine triphosphate (ATP)-binding cassette (ABC) transporter. It was designed to improve the oral bioavailability of drugs that are P-gp substrates that can be pumped out of cells by P-gp, resulting in drug resistance. The combination of oral paclitaxel and encequidar is being developed for cancer treatment. Paclitaxel cannot be administered orally, because it is a substrate of the P-glycoprotein (P-gp), and the bioavailability of paclitaxel is improved when oral paclitaxel is administered with the highly specific, potent P-gp inhibitor encequidar. 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 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. 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	C39H40N6O10S
Molecular Weight	784.834108352661
Exact Mass	784.252
CAS #	849675-87-2
Related CAS #	Encequidar;849675-66-7;Encequidar mesylate hydrochloride;2097125-58-9
PubChem CID	76971350
Appearance	Light yellow to yellow solid powder
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	14
Rotatable Bond Count	11
Heavy Atom Count	56
Complexity	1310
Defined Atom Stereocenter Count	0
InChi Key	PEKXWELLWNPUOK-UHFFFAOYSA-N
InChi Code	InChI=1S/C38H36N6O7.CH4O3S/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)51-361-5(2,3)4/h5-12,17-21H,13-16,22H2,1-4H3,(H,39,46)1H3,(H,2,3,4)
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 methanesulfonate
Synonyms	HM-30181HM30181 HM 30181 HM-30181 mesylate
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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.
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	Encequidar (HM30181) therapy at concentrations of 0.1 or 1 nM led to a 20% and 42% reduction in survival with 100 nM and 1000 nM NSC 125973 administration, respectively [2].
ln Vivo	When Encequidar (HM30181) microcapsules and powder were given simultaneously, the plasma concentrations were greater; this difference was statistically significant and lasted between one and two hours. The AUC value was approximately 1.6 times higher and the Tmax of microcapsules was approximately 1.7 times faster than that of powder (2.5±0.6 vs. 4.3±0.9 h; 107.7±20.1 vs. 64.3±18.0 h ng/mL). Encequidar (HM30181) may have improved overall and absorbed more quickly in microencapsulated form because of its crystals changing into an amorphous state and its particle size being reduced, which has greatly increased its water solubility and dissolution [1].
References	[1]. Effect of HM30181 mesylate salt-loaded microcapsules on the oral absorption of NSC 125973 as a novel P-glycoprotein inhibitor. Int J Pharm. 2016 Jun 15;506(1-2):93-101. [2]. Response of brain specific microenvironment to P-glycoprotein inhibitor: an important factor determining therapeutic effect of P-glycoprotein inhibitor on brain metastatic tumors. Int J Oncol. 2008 Oct;33(4):705-12.
Additional Infomation	See also: Encequidar Mesylate (annotation moved to).

Solubility Data

Solubility (In Vitro)

DMSO : ~25 mg/mL (~31.85 mM)

Solubility (In Vivo)

Solubility in Formulation 1: 2.5 mg/mL (3.19 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.2742 mL	6.3708 mL	12.7416 mL
	5 mM	0.2548 mL	1.2742 mL	2.5483 mL
	10 mM	0.1274 mL	0.6371 mL	1.2742 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.