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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
Molecular Formula C38H36N6O7
Molecular Weight 688.7284
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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
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
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)
Substance Class Chemical
Created
by admin
on Sat Dec 16 10:53:13 GMT 2023
Edited
by admin
on Sat Dec 16 10:53:13 GMT 2023
Record UNII
K4I4I996O4
Record Status Validated (UNII)
Record Version
  • Download
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
Related Record Type Details
CYTOCHROME P450 3A4
METABOLIC ENZYME -> SUBSTRATE
MAJOR
MRP-1
TRANSPORTER -> NON-INHIBITOR
CYTOCHROME P450 3A4
METABOLIC ENZYME -> NON-INHIBITOR
MULTIDRUG RESISTANCE PROTEIN 1
TARGET -> INHIBITOR
The P-gp inhibitory effect of oral HM30181 is exerted only locally in the luminal endothelium of the gastrointestinal tract when the dose is ≤15 mg.
IC50
Structure of ENCEQUIDAR MESYLATE ANHYDROUS
SALT/SOLVATE -> PARENT
Structure of ENCEQUIDAR MESYLATE
SALT/SOLVATE -> PARENT
MRP-2
TRANSPORTER -> NON-INHIBITOR
MRP-3
TRANSPORTER -> NON-INHIBITOR
Structure of ENCEQUIDAR HYDROCHLORIDE
SALT/SOLVATE -> PARENT
Related Record Type Details
Structure of ENCEQUIDAR, DES(CHROMOCARB)-
METABOLITE -> PARENT
Related Record Type Details
Structure of ENCEQUIDAR
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
AUC 0-LAST PHARMACOKINETIC DOSE
PHARMACOKINETIC
ROUTE OF ADMINISTRATION
PHARMACOKINETIC
Cmax PHARMACOKINETIC DOSE
PHARMACOKINETIC
ROUTE OF ADMINISTRATION
PHARMACOKINETIC
Tmax PHARMACOKINETIC DOSE
PHARMACOKINETIC
ROUTE OF ADMINSITRATION
PHARMACOKINETIC
Cmax PHARMACOKINETIC DOSE
PHARMACOKINETIC
ROUTE OF ADMINISTRATION
PHARMACOKINETIC
NIH
NCATS
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HHS VULNERABILITY DISCLOSURE
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