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)
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 |
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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 |
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/ |
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weak | ||||
weak | ||||
weak |
PubMed
Title | Date | PubMed |
---|---|---|
Effect of coadministration of ketoconazole, a strong CYP3A4 inhibitor, on pharmacokinetics and tolerability of motesanib diphosphate (AMG 706) in patients with advanced solid tumors. | 2008 Oct |
|
Novel therapies in breast cancer: what is new from ASCO 2008. | 2008 Oct 1 |
|
Targeting RET for thyroid cancer therapy. | 2009 Feb 1 |
|
Pretargeted radioimmunotherapy in the treatment of metastatic medullary thyroid cancer. | 2009 Sep |
|
Present and future evolution of advanced breast cancer therapy. | 2010 |
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Molecular and other novel advances in treatment of metastatic epithelial and medullary thyroid cancers. | 2010 |
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Targeting angiogenesis with multitargeted tyrosine kinase inhibitors in the treatment of non-small cell lung cancer. | 2010 |
|
Phase 1b study of motesanib, an oral angiogenesis inhibitor, in combination with carboplatin/paclitaxel and/or panitumumab for the treatment of advanced non-small cell lung cancer. | 2010 Jan 1 |
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Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors. | 2010 Jul 15 |
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A phase Ib study of AMG 102 in combination with bevacizumab or motesanib in patients with advanced solid tumors. | 2010 May 1 |
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Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. | 2010 May 5 |
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Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. | 2010 Nov 24 |
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Safety and pharmacokinetics of motesanib in combination with panitumumab and gemcitabine-Cisplatin in patients with advanced cancer. | 2011 |
|
Comprehensive analysis of kinase inhibitor selectivity. | 2011 Oct 30 |
|
Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors. | 2012 Dec 27 |
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
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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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SS-13
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DB05575
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SUB93453
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U1JK633AYI
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11667893
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)