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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 of ENCEQUIDAR

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

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

Unknown
139594
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8297
 0.63 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Phase III
656
Unknown

Approved Use

Unknown
Primary
Phase II
1132
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
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

AUC

ValueDoseCo-administeredAnalytePopulation
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
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
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

Doses

DosePopulationAdverse 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

AEs

AESignificanceDosePopulation
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

PubMed

TitleDatePubMed
Metabolism of a new P-glycoprotein inhibitor HM-30181 in rats using liquid chromatography/electrospray mass spectrometry.
2006
Simultaneous determination of paclitaxel and a new P-glycoprotein inhibitor HM-30181 in rat plasma by liquid chromatography with tandem mass spectrometry.
2006 Mar
Characterization of human liver cytochrome P-450 enzymes involved in the O-demethylation of a new P-glycoprotein inhibitor HM-30181.
2007 Aug
Selective inhibition of MDR1 (ABCB1) by HM30181 increases oral bioavailability and therapeutic efficacy of paclitaxel.
2010 Feb 10
Patents

Patents

07625926
6
08680277
4
20070072900
4
20120330020
4
20140148602
4

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
INN   USAN  
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
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
NCI_THESAURUS C2140
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
Code System Code Type Description
PUBCHEM
11399764
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
PRIMARY
EPA CompTox
DTXSID501100387
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
PRIMARY
EVMPD
SUB197131
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
PRIMARY
FDA UNII
K4I4I996O4
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
PRIMARY
DRUG BANK
DB14070
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
PRIMARY
CAS
849675-66-7
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
PRIMARY
NCI_THESAURUS
C111994
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
PRIMARY
INN
10861
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
PRIMARY
USAN
HI-91
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
PRIMARY
SMS_ID
100000182801
Created by admin on Sat Dec 16 10:53:14 GMT 2023 , Edited by admin on Sat Dec 16 10:53:14 GMT 2023
PRIMARY
ACTIVE MOIETY
Structure of ENCEQUIDAR
SALT/SOLVATE (PARENT)
Structure of ENCEQUIDAR MESYLATE
SALT/SOLVATE (PARENT)
Structure of ENCEQUIDAR HYDROCHLORIDE
NIH
NCATS
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