ENCEQUIDAR

Details

Stereochemistry	ACHIRAL
Molecular Formula	C38H36N6O7
Molecular Weight	688.7284
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC2=C(CN(CCC3=CC=C(C=C3)N4N=NC(=N4)C5=CC(OC)=C(OC)C=C5NC(=O)C6=CC(=O)C7=C(O6)C=CC=C7)CC2)C=C1OC

InChI

InChIKey=AHJUHHDDCJQACA-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19903471 | http://www.athenex.com/oncology-innovation/oral-absorption-platform/oraxol-an-oral-formulation-of-paclitaxel/

HM-30181 is a highly selective and potent inhibitor of Multi-drug resistance 1 (MDR1, ABCB1), also known as P-glycoprotein (P-gp). Co-administration of HM30181 greatly increased oral bioavailability of tubulin-stabilizing chemotherapeutic agent paclitaxel. Oraxol is an oral dosage form of paclitaxel administered orally with the HM30181A molecule. Oraxol offers patients with paclitaxel-responsive tumors the possibility of oral therapy without the requirement for premedication to prevent infusion-related hypersensitivity-type reactions. Current clinical data suggests the promising potential of a better clinical response and tolerability profile, which can likely to be attributed to the better pharmacokinetic profile achieved. Oraxol is presently in a Phase 3 trial in metastatic breast cancer and poised to enter into a combination study for treatment of advanced gastric cancer with ramucirumab through a clinical trial collaboration with Eli Lilly and Company.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
P-glycoprotein 1 54 Target ID: CHEMBL4302 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19903471	Inhibitor 8297		0.63 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Breast cancer 434 Sources: http://www.athenex.com/oncology-innovation/oral-absorption-platform/oraxol-an-oral-formulation-of-paclitaxel/	Primary		Phase III 656	Unknown Approved Use Unknown
Gastric cancer 53 Sources: http://www.athenex.com/oncology-innovation/oral-absorption-platform/oraxol-an-oral-formulation-of-paclitaxel/	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
13.4 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	180 mg 1 times / day multiple, oral dose: 180 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
22.5 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	360 mg 1 times / day multiple, oral dose: 360 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
16.2 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
6.6 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	900 mg single, oral dose: 900 mg route of administration: Oral experiment type: SINGLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
5.2 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
4 μg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	360 mg single, oral dose: 360 mg route of administration: Oral experiment type: SINGLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
233.1 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	180 mg 1 times / day multiple, oral dose: 180 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
233.1 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	360 mg 1 times / day multiple, oral dose: 360 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
262.3 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1112.8 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	900 mg single, oral dose: 900 mg route of administration: Oral experiment type: SINGLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
556.8 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
697 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	360 mg single, oral dose: 360 mg route of administration: Oral experiment type: SINGLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
215.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	180 mg 1 times / day multiple, oral dose: 180 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
198 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	360 mg 1 times / day multiple, oral dose: 360 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
153.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	60 mg 1 times / day multiple, oral dose: 60 mg route of administration: Oral experiment type: MULTIPLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
122.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	900 mg single, oral dose: 900 mg route of administration: Oral experiment type: SINGLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
75.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
169.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22284902/	360 mg single, oral dose: 360 mg route of administration: Oral experiment type: SINGLE co-administered:	HM-30181 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
360 mg 1 times / day multiple, oral Highest studied dose Dose: 360 mg, 1 times / day Route: oral Route: multiple Dose: 360 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	Other AEs: Loose stools, Epigastric discomfort... Other AEs: Loose stools (12.5%) Epigastric discomfort (12.5%) Anorexia (12.5%) Diarrhea (50%) Fatigue (12.5%) Abdominal pain (50%) Dizziness (12.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/
900 mg single, oral (unknown) Highest studied dose Dose: 900 mg Route: oral Route: single Dose: 900 mg Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	Other AEs: Dizziness... Other AEs: Dizziness (12.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/

AEs

AE	Significance	Dose	Population
Anorexia	12.5%	360 mg 1 times / day multiple, oral Highest studied dose Dose: 360 mg, 1 times / day Route: oral Route: multiple Dose: 360 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/
Dizziness	12.5%	360 mg 1 times / day multiple, oral Highest studied dose Dose: 360 mg, 1 times / day Route: oral Route: multiple Dose: 360 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/
Epigastric discomfort	12.5%	360 mg 1 times / day multiple, oral Highest studied dose Dose: 360 mg, 1 times / day Route: oral Route: multiple Dose: 360 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/
Fatigue	12.5%	360 mg 1 times / day multiple, oral Highest studied dose Dose: 360 mg, 1 times / day Route: oral Route: multiple Dose: 360 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/
Loose stools	12.5%	360 mg 1 times / day multiple, oral Highest studied dose Dose: 360 mg, 1 times / day Route: oral Route: multiple Dose: 360 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/
Abdominal pain	50%	360 mg 1 times / day multiple, oral Highest studied dose Dose: 360 mg, 1 times / day Route: oral Route: multiple Dose: 360 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/
Diarrhea	50%	360 mg 1 times / day multiple, oral Highest studied dose Dose: 360 mg, 1 times / day Route: oral Route: multiple Dose: 360 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/
Dizziness	12.5%	900 mg single, oral (unknown) Highest studied dose Dose: 900 mg Route: oral Route: single Dose: 900 mg Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/	healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/22284902/

PubMed

Title	Date	PubMed
Metabolism of a new P-glycoprotein inhibitor HM-30181 in rats using liquid chromatography/electrospray mass spectrometry.	2006	16586459
Simultaneous determination of paclitaxel and a new P-glycoprotein inhibitor HM-30181 in rat plasma by liquid chromatography with tandem mass spectrometry.	2006 Mar	16605080
Characterization of human liver cytochrome P-450 enzymes involved in the O-demethylation of a new P-glycoprotein inhibitor HM-30181.	2007 Aug	17654255
Response of brain specific microenvironment to P-glycoprotein inhibitor: an important factor determining therapeutic effect of P-glycoprotein inhibitor on brain metastatic tumors.	2008 Oct	18813783
Selective inhibition of MDR1 (ABCB1) by HM30181 increases oral bioavailability and therapeutic efficacy of paclitaxel.	2010 Feb 10	19903471

Patents

Sample Use Guides

In Vivo Use Guide

HM30181 was well tolerated after oral administration within the dose range evaluated (180-, 360-, 600-, and 900-mg single-dose groups and 60-, 180-, and 360-mg multiple-dose groups), with the exception of the repeated administration of 360 mg, for which gastrointestinal disorders were frequently reported. Oraxol (paclitaxel - supplied as 30-mg capsules HM30181 methansulfonate monohydrate - supplied as 15-mg HM30181AK-US) is studying in a Phase 3 trial for the treatment of breast cancer, however, treatment regimen is unknown.

Route of Administration: Oral

In Vitro Use Guide

HM-30181 effectively blocked transepithelial transport of paclitaxel in MDCK monolayers (IC(50)=35.4nM)

Name

Type

Language

ENCEQUIDAR

Official Name

English

ENCEQUIDAR [USAN]

Common Name

English

Encequidar [WHO-DD]

Common Name

English

encequidar [INN]

Common Name

English

N-[2-[2-[4-[2-(3,4-Dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)ethyl]phenyl]-2H-tetrazol-5-yl]-4,5-dimethoxyphenyl]-4-oxo-4H-1-benzopyran-2-carboxamide

Systematic Name

English

HM-30181

Code

English

P-GLYCOPROTEIN INHIBITOR HM30181AK

Common Name

English

4-OXO-4H-CHROMENE-2-CARBOXYLIC ACID (2-(2-4-(2-(6,7-DIMETHOXY-3,4-DIHYDRO-1H-ISOQUINOLIN-2-YL)-ETHYL)-PHENYL-2H-TETRAZOL-5-YL)-4,5-DIMETHOXY-PHENYL)-AMIDE

Systematic Name

English

HM30181AK

Code

English

PGP INHIBITOR HM30181AK

Common Name

English

4H-1-BENZOPYRAN-2-CARBOXAMIDE, N-(2-(2-(4-(2-(3,4-DIHYDRO-6,7-DIMETHOXY-2(1H)-ISOQUINOLINYL)ETHYL)PHENYL)-2H-TETRAZOL-5-YL)-4,5-DIMETHOXYPHENYL)-4-OXO-

Systematic Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

594217