Details
Stereochemistry | ACHIRAL |
Molecular Formula | C22H23N5O |
Molecular Weight | 373.4509 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC1(C)CNC2=C1C=CC(NC(=O)C3=CC=CN=C3NCC4=CC=NC=C4)=C2
InChI
InChIKey=RAHBGWKEPAQNFF-UHFFFAOYSA-N
InChI=1S/C22H23N5O/c1-22(2)14-26-19-12-16(5-6-18(19)22)27-21(28)17-4-3-9-24-20(17)25-13-15-7-10-23-11-8-15/h3-12,26H,13-14H2,1-2H3,(H,24,25)(H,27,28)
Molecular Formula | C22H23N5O |
Molecular Weight | 373.4509 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
DescriptionSources: http://adisinsight.springer.com/drugs/800011016Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/16951187
Sources: http://adisinsight.springer.com/drugs/800011016
Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/16951187
Motesanib (AMG 706), a novel nicotinamide, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4 and Kit receptors. Motesanib was expected to reduce vascular permeability and blood flow in human tumours. A phase III trial of motesanib in combination with paclitaxel and carboplatin in non-squamous NSCLC has been terminated by Takeda and subsequently the development was discontinued. Motesanib has also been investigated up to phase II in breast, thyroid, colorectal and gastrointestinal stromal tumours. However, development has been discontinued in these indications.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1868 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=16951187 |
2.0 nM [IC50] | ||
Target ID: CHEMBL279 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16951187 |
3.0 nM [IC50] | ||
Target ID: CHEMBL1955 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16951187 |
6.0 nM [IC50] | ||
Target ID: CHEMBL1936 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16951187 |
8.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
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 |
Doses
Dose | Population | Adverse events |
---|---|---|
175 mg 1 times / day multiple, oral Highest studied dose Dose: 175 mg, 1 times / day Route: oral Route: multiple Dose: 175 mg, 1 times / day Sources: Page: p.2371 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.2371 |
DLT: Encephalopathy, Fatigue... Dose limiting toxicities: Encephalopathy (grade 3, 16.7%) Sources: Page: p.2371Fatigue (grade 3, 16.7%) Hyperbilirubinemia (grade 3, 16.7%) |
125 mg 1 times / day multiple, oral MTD Dose: 125 mg, 1 times / day Route: oral Route: multiple Dose: 125 mg, 1 times / day Sources: Page: p.5 |
unhealthy, ADULT n = 22 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 22 Sources: Page: p.5 |
Disc. AE: Posterior reversible encephalopathy syndrome... AEs leading to discontinuation/dose reduction: Posterior reversible encephalopathy syndrome (18.2%) Sources: Page: p.5 |
125 mg 1 times / day multiple, oral MTD Dose: 125 mg, 1 times / day Route: oral Route: multiple Dose: 125 mg, 1 times / day Sources: Page: p.2371 |
unhealthy, ADULT n = 28 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 28 Sources: Page: p.2371 |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Encephalopathy | grade 3, 16.7% DLT, Disc. AE |
175 mg 1 times / day multiple, oral Highest studied dose Dose: 175 mg, 1 times / day Route: oral Route: multiple Dose: 175 mg, 1 times / day Sources: Page: p.2371 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.2371 |
Fatigue | grade 3, 16.7% DLT, Disc. AE |
175 mg 1 times / day multiple, oral Highest studied dose Dose: 175 mg, 1 times / day Route: oral Route: multiple Dose: 175 mg, 1 times / day Sources: Page: p.2371 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.2371 |
Hyperbilirubinemia | grade 3, 16.7% DLT, Disc. AE |
175 mg 1 times / day multiple, oral Highest studied dose Dose: 175 mg, 1 times / day Route: oral Route: multiple Dose: 175 mg, 1 times / day Sources: Page: p.2371 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.2371 |
Posterior reversible encephalopathy syndrome | 18.2% Disc. AE |
125 mg 1 times / day multiple, oral MTD Dose: 125 mg, 1 times / day Route: oral Route: multiple Dose: 125 mg, 1 times / day Sources: Page: p.5 |
unhealthy, ADULT n = 22 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 22 Sources: Page: p.5 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
no | ||||
weak [Inhibition 50 uM] | ||||
yes [Inhibition 1 uM] | ||||
yes [Inhibition 1 uM] | ||||
yes [Inhibition 50 uM] | ||||
yes | ||||
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
major | ||||
major | ||||
minor | ||||
minor | ||||
minor | ||||
moderate | yes (co-administration study) Comment: Ketoconazole increased AUC(0-24h) and Cmax by 86% and 35%. Sources: https://pubmed.ncbi.nlm.nih.gov/18574557/ |
|||
weak | ||||
weak | ||||
weak |
PubMed
Title | Date | PubMed |
---|---|---|
Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors. | 2009 Jan 1 |
|
Pretargeted radioimmunotherapy in the treatment of metastatic medullary thyroid cancer. | 2009 Sep |
|
Present and future evolution of advanced breast cancer therapy. | 2010 |
|
Phase II study of motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate. | 2010 Apr |
|
Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors. | 2010 Jul 15 |
|
Axitinib: The evidence of its potential in the treatment of advanced thyroid cancer. | 2010 Jun 15 |
|
Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? | 2010 Mar |
|
Development of a modeling framework to simulate efficacy endpoints for motesanib in patients with thyroid cancer. | 2010 Nov |
|
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. | 2010 Nov 24 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: http://adisinsight.springer.com/drugs/800011016
50-125 mg per day. Motesanib appeared to induce a dose-dependent biological response in an ongoing phase I trial in patients with advanced solid tumours. A reduction in soluble VEGF-receptor 2 (KDR) correlated with the change in tumour size at day 50. In a phase II trial, motesanib at doses up to 125 mg/day showed anti-tumour activity among patients with advanced malignancy.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16951187
Motesanib (AMG-706) potently inhibited VEGF-induced proliferation of HUVECs with IC50 values of 10 nM
Substance Class |
Chemical
Created
by
admin
on
Edited
Thu Jul 06 00:43:20 UTC 2023
by
admin
on
Thu Jul 06 00:43:20 UTC 2023
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Record UNII |
U1JK633AYI
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Record Status |
Validated (UNII)
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NCI_THESAURUS |
C1967
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453562-69-1
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DTXSID10196488
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M7636
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CHEMBL572881
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C71896
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100000141571
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8828
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MOTESANIB
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U1JK633AYI
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11667893
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