Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C27H41NO5S |
Molecular Weight | 491.683 |
Optical Activity | ( - ) |
Defined Stereocenters | 5 / 5 |
E/Z Centers | 1 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
C[C@H]1CCCC(C)=CC[C@H](OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@H]1O)C(\C)=C\C2=CSC(C)=N2
InChI
InChIKey=XOZIUKBZLSUILX-GIQCAXHBSA-N
InChI=1S/C27H41NO5S/c1-16-9-8-10-17(2)25(31)19(4)26(32)27(6,7)23(29)14-24(30)33-22(12-11-16)18(3)13-21-15-34-20(5)28-21/h11,13,15,17,19,22-23,25,29,31H,8-10,12,14H2,1-7H3/b16-11-,18-13+/t17-,19+,22-,23-,25-/m0/s1
Epothilone D (KOS-862 or BMS-241027) is an intermediary obtained in the synthesis of members of the epothilone family and is a small-molecule microtubule stabilizer. It was investigated in Phase II trials in colorectal, metastatic breast and non-small-cell lung cancers. However, development was discontinued in 2007 in favor of a second-generation analog with a better safety profile. This drug also was studied for the treatment of Alzheimer's disease. The study ended in October 2013, and evaluation of epothilone D for Alzheimer's disease was subsequently discontinued. The mechanism by which epothilones induce microtubule polymerization appears to be similar to that of paclitaxel, in that epothilones compete with paclitaxel for binding to microtubules and suppress microtubule dynamics in a manner similar to that of paclitaxel.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20943926
Curator's Comment: Known to be CNS penetrant in rat. Human data not available
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: microtubules Sources: https://www.ncbi.nlm.nih.gov/pubmed/15143095 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2737.2 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19775943 |
125 mg/m² single, intravenous dose: 125 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
EPOTHILONE D plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
4037 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22072399 |
100 mg/m² 1 times / week multiple, intravenous dose: 100 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: |
EPOTHILONE D plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
3001.6 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19775943 |
125 mg/m² single, intravenous dose: 125 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
EPOTHILONE D HYDROLYTIC METABOLITE plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
9451.7 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19775943 |
125 mg/m² single, intravenous dose: 125 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
EPOTHILONE D plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
12093 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22072399 |
100 mg/m² 1 times / week multiple, intravenous dose: 100 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: |
EPOTHILONE D plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
16928.2 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19775943 |
125 mg/m² single, intravenous dose: 125 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
EPOTHILONE D HYDROLYTIC METABOLITE plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
15 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19775943 |
125 mg/m² single, intravenous dose: 125 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
EPOTHILONE D plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
9.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22072399 |
100 mg/m² 1 times / week multiple, intravenous dose: 100 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered: |
EPOTHILONE D plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
23.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19775943 |
125 mg/m² single, intravenous dose: 125 mg/m² route of administration: Intravenous experiment type: SINGLE co-administered: |
EPOTHILONE D HYDROLYTIC METABOLITE plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
120 mg/m2 3 times / 3 weeks multiple, intravenous (total daily dose) Highest studied dose Dose: 120 mg/m2, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 120 mg/m2, 3 times / 3 weeks Sources: |
unhealthy n = 2 Health Status: unhealthy Condition: solid tumors Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: |
DLT: Visual Hallucination, Dehydration... Other AEs: Syncope... Dose limiting toxicities: Visual Hallucination (1 pt) Other AEs:Dehydration (1 pt) Diarrhea (severe, 1 pt) Nausea (severe, 1 pt) Vomiting (severe, 1 pt) Syncope (1 pt) Sources: |
100 mg/m2 2 times / 3 weeks multiple, intravenous (total daily dose) Studied dose Dose: 100 mg/m2, 2 times / 3 weeks Route: intravenous Route: multiple Dose: 100 mg/m2, 2 times / 3 weeks Sources: |
unhealthy n = 10 Health Status: unhealthy Condition: solid tumours Sex: M+F Food Status: UNKNOWN Population Size: 10 Sources: |
DLT: visual hallucination, Peripheral sensory neuropathy... Dose limiting toxicities: visual hallucination (grade 2, 2 patients) Sources: Peripheral sensory neuropathy (grade 2, 2 patients) |
100 mg/m2 3 times / 3 weeks multiple, intravenous (total daily dose) Studied dose Dose: 100 mg/m2, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 100 mg/m2, 3 times / 3 weeks Sources: |
unhealthy n = 10 Health Status: unhealthy Condition: tumor cancer Sex: M+F Food Status: UNKNOWN Population Size: 10 Sources: |
DLT: Peripheral sensory neuropathy... Dose limiting toxicities: Peripheral sensory neuropathy (grade 2, 1 pt) Sources: |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Syncope | 1 pt | 120 mg/m2 3 times / 3 weeks multiple, intravenous (total daily dose) Highest studied dose Dose: 120 mg/m2, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 120 mg/m2, 3 times / 3 weeks Sources: |
unhealthy n = 2 Health Status: unhealthy Condition: solid tumors Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: |
Visual Hallucination | 1 pt DLT |
120 mg/m2 3 times / 3 weeks multiple, intravenous (total daily dose) Highest studied dose Dose: 120 mg/m2, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 120 mg/m2, 3 times / 3 weeks Sources: |
unhealthy n = 2 Health Status: unhealthy Condition: solid tumors Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: |
Dehydration | 1 pt DLT, Disc. AE |
120 mg/m2 3 times / 3 weeks multiple, intravenous (total daily dose) Highest studied dose Dose: 120 mg/m2, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 120 mg/m2, 3 times / 3 weeks Sources: |
unhealthy n = 2 Health Status: unhealthy Condition: solid tumors Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: |
Diarrhea | severe, 1 pt DLT |
120 mg/m2 3 times / 3 weeks multiple, intravenous (total daily dose) Highest studied dose Dose: 120 mg/m2, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 120 mg/m2, 3 times / 3 weeks Sources: |
unhealthy n = 2 Health Status: unhealthy Condition: solid tumors Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: |
Nausea | severe, 1 pt DLT |
120 mg/m2 3 times / 3 weeks multiple, intravenous (total daily dose) Highest studied dose Dose: 120 mg/m2, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 120 mg/m2, 3 times / 3 weeks Sources: |
unhealthy n = 2 Health Status: unhealthy Condition: solid tumors Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: |
Vomiting | severe, 1 pt DLT |
120 mg/m2 3 times / 3 weeks multiple, intravenous (total daily dose) Highest studied dose Dose: 120 mg/m2, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 120 mg/m2, 3 times / 3 weeks Sources: |
unhealthy n = 2 Health Status: unhealthy Condition: solid tumors Sex: M+F Food Status: UNKNOWN Population Size: 2 Sources: |
Peripheral sensory neuropathy | grade 2, 2 patients DLT |
100 mg/m2 2 times / 3 weeks multiple, intravenous (total daily dose) Studied dose Dose: 100 mg/m2, 2 times / 3 weeks Route: intravenous Route: multiple Dose: 100 mg/m2, 2 times / 3 weeks Sources: |
unhealthy n = 10 Health Status: unhealthy Condition: solid tumours Sex: M+F Food Status: UNKNOWN Population Size: 10 Sources: |
visual hallucination | grade 2, 2 patients DLT |
100 mg/m2 2 times / 3 weeks multiple, intravenous (total daily dose) Studied dose Dose: 100 mg/m2, 2 times / 3 weeks Route: intravenous Route: multiple Dose: 100 mg/m2, 2 times / 3 weeks Sources: |
unhealthy n = 10 Health Status: unhealthy Condition: solid tumours Sex: M+F Food Status: UNKNOWN Population Size: 10 Sources: |
Peripheral sensory neuropathy | grade 2, 1 pt DLT |
100 mg/m2 3 times / 3 weeks multiple, intravenous (total daily dose) Studied dose Dose: 100 mg/m2, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 100 mg/m2, 3 times / 3 weeks Sources: |
unhealthy n = 10 Health Status: unhealthy Condition: tumor cancer Sex: M+F Food Status: UNKNOWN Population Size: 10 Sources: |
Sample Use Guides
In Vivo Use Guide
Sources: http://www.alzforum.org/therapeutics/epothilone-d
Alzheimer's Disease: BMS-241027 (Epothilone D) in 40 patients with mild Alzheimer's disease whose MMSE at screening was between 20 and 26. The trial compares 0.003, 0.01, and 0.03 mg/kg infused once a week for nine weeks to placebo.
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/14686728
The effects of 1, 10 and 100 nM concentrations of epothilone (EPO) D in four malignant human glioma cell lines were measured using a microtiter-tetrazolium assay. In all four human glioma cell lines, 10 and 100 nM concentrations of the drug, applied for 96 h, leading to a highly significant decrease in the viable cell number (p < 0.001). A mean reduction of the viable cell number between 30% and 40% (60% and 90%) was observed for a drug concentration of 10 nM (100 nM). A round cell morphology occurred in most EPO treated cells and the organized network of microtubules was shrunk in these round cells. These results prove that EPOs have antiproliferative effects in glioma cells and affect their tubulin cytoskeleton, as it was previously observed in several types of carcinoma cells.
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NCI_THESAURUS |
C1922
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NCI_THESAURUS |
C67437
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29579
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DB01873
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C2672
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ACTIVE MOIETY