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
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)
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 |
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 |
---|---|---|---|
Target ID: CHEMBL4302 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19903471 |
0.63 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | 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 | Co-administered | 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 |
T1/2
Value | Dose | Co-administered | 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: |
healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: |
Other AEs: Loose stools, Epigastric discomfort... Other AEs: Loose stools (12.5%) Sources: Epigastric discomfort (12.5%) Anorexia (12.5%) Diarrhea (50%) Fatigue (12.5%) Abdominal pain (50%) Dizziness (12.5%) |
900 mg single, oral (unknown) Highest studied dose |
healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: |
Other AEs: Dizziness... |
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: |
healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: |
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: |
healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: |
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: |
healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: |
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: |
healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: |
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: |
healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: |
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: |
healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: |
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: |
healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: |
Dizziness | 12.5% | 900 mg single, oral (unknown) Highest studied dose |
healthy n = 8 Health Status: healthy Sex: M Food Status: FASTED Population Size: 8 Sources: |
Sample Use Guides
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19903471
HM-30181 effectively blocked transepithelial transport of paclitaxel in MDCK monolayers (IC(50)=35.4nM)
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 10:53:13 GMT 2023
by
admin
on
Sat Dec 16 10:53:13 GMT 2023
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Record UNII |
K4I4I996O4
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Record Status |
Validated (UNII)
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Record Version |
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-
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Official Name | English | ||
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Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
594217
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NCI_THESAURUS |
C2140
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11399764
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DTXSID501100387
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SUB197131
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K4I4I996O4
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DB14070
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849675-66-7
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C111994
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10861
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HI-91
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100000182801
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Related Record | Type | Details | ||
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METABOLIC ENZYME -> SUBSTRATE |
MAJOR
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TRANSPORTER -> NON-INHIBITOR |
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METABOLIC ENZYME -> NON-INHIBITOR | |||
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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
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SALT/SOLVATE -> PARENT | |||
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SALT/SOLVATE -> PARENT | |||
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TRANSPORTER -> NON-INHIBITOR | |||
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TRANSPORTER -> NON-INHIBITOR | |||
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SALT/SOLVATE -> PARENT |
Related Record | Type | Details | ||
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METABOLITE -> PARENT |
Related Record | Type | Details | ||
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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AUC 0-LAST | PHARMACOKINETIC |
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DOSE PHARMACOKINETIC PHARMACOKINETIC |
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Cmax | PHARMACOKINETIC |
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DOSE PHARMACOKINETIC PHARMACOKINETIC |
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Tmax | PHARMACOKINETIC |
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DOSE PHARMACOKINETIC PHARMACOKINETIC |
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Cmax | PHARMACOKINETIC |
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DOSE PHARMACOKINETIC PHARMACOKINETIC |
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