MOTESANIB DIPHOSPHATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H23N5O.2H3O4P
Molecular Weight	569.4413
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OP(O)(O)=O.OP(O)(O)=O.CC1(C)CNC2=C1C=CC(NC(=O)C3=CC=CN=C3NCC4=CC=NC=C4)=C2

InChI

InChIKey=ONDPWWDPQDCQNJ-UHFFFAOYSA-N

InChI=1S/C22H23N5O.2H3O4P/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;2*1-5(2,3)4/h3-12,26H,13-14H2,1-2H3,(H,24,25)(H,27,28);2*(H3,1,2,3,4)

HIDE SMILES / InChI

Description
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	Potency
Vascular endothelial growth factor receptor 1 41 Target ID: CHEMBL1868 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=16951187	Inhibitor 8297	2.0 nM [IC50]
Vascular endothelial growth factor receptor 2 104 Target ID: CHEMBL279 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16951187	Inhibitor 8297	3.0 nM [IC50]
Vascular endothelial growth factor receptor 3 41 Target ID: CHEMBL1955 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16951187	Inhibitor 8297	6.0 nM [IC50]
Stem cell growth factor receptor 53 Target ID: CHEMBL1936 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16951187	Inhibitor 8297	8.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 206 Sources: http://adisinsight.springer.com/drugs/800011016	Primary	Phase III 656	Unknown Approved Use Unknown
Thyroid cancer 16 Sources: http://adisinsight.springer.com/drugs/800011016	Primary	Phase II 1132	Unknown Approved Use Unknown
Ovarian cancer 157 Sources: http://adisinsight.springer.com/drugs/800011016	Primary	Phase II 1132	Unknown Approved Use Unknown
Colorectal cancer 101 Sources: http://adisinsight.springer.com/drugs/800011016	Primary	Phase I 428	Unknown Approved Use Unknown

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: https://pubmed.ncbi.nlm.nih.gov/17557949 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: https://pubmed.ncbi.nlm.nih.gov/17557949 Page: p.2371	DLT: Encephalopathy, Fatigue... Dose limiting toxicities: Encephalopathy (grade 3, 16.7%) Fatigue (grade 3, 16.7%) Hyperbilirubinemia (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/17557949 Page: p.2371
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: https://pubmed.ncbi.nlm.nih.gov/23321064 Page: p.5	unhealthy, ADULT n = 22 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/23321064 Page: p.5	Disc. AE: Posterior reversible encephalopathy syndrome... AEs leading to discontinuation/dose reduction: Posterior reversible encephalopathy syndrome (18.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/23321064 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: https://pubmed.ncbi.nlm.nih.gov/17557949 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: https://pubmed.ncbi.nlm.nih.gov/17557949 Page: p.2371	Sources: https://pubmed.ncbi.nlm.nih.gov/17557949 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: https://pubmed.ncbi.nlm.nih.gov/17557949 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: https://pubmed.ncbi.nlm.nih.gov/17557949 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: https://pubmed.ncbi.nlm.nih.gov/17557949 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: https://pubmed.ncbi.nlm.nih.gov/17557949 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: https://pubmed.ncbi.nlm.nih.gov/17557949 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: https://pubmed.ncbi.nlm.nih.gov/17557949 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: https://pubmed.ncbi.nlm.nih.gov/23321064 Page: p.5	unhealthy, ADULT n = 22 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/23321064 Page: p.5

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 substrate 1737	inhibitor 1767	inhibitor 1852 substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 MRP1 106 MRP10 2 CYP1A2 1524 P-gp 1461	UGT1A1 418 CYP1A1 349 CYP2B6 664 UGT 192 CYP3A5 395 UGT1A4 347 CYP3A7 110

Drug as perpetrator

Target	Modality	Activity
MRP1 172	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24937702/	no
MRP10 2	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24937702/	no
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24462920/	weak [Inhibition 50 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24462920/	yes [Inhibition 1 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24462920/	yes [Inhibition 1 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24462920/	yes [Inhibition 50 uM]
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24937702/	yes
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24937702/	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
UGT 192	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/18574557/	major
UGT1A4 347	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	major
CYP1A1 349	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	minor
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	minor
UGT1A1 418	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	minor
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/18574557/	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/
CYP2B6 664	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	weak
CYP3A5 395	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	weak
CYP3A7 110	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	weak

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P00D8H0	https://www.1pchem.com/search?query=1P00D8H0
1PlusChem LLC	1P00G31L	https://www.1pchem.com/search?query=1P00G31L
AChemBlock	Q70236	http://www.achemblock.com/catalogsearch/result/?q=Q70236
AK Scientific	SYN1055	https://aksci.com/item_detail.php?cat=SYN1055
AK Scientific	SYN5718	https://aksci.com/item_detail.php?cat=SYN5718
AK Scientific	X4931	https://aksci.com/item_detail.php?cat=X4931
AK Scientific	X7466	https://aksci.com/item_detail.php?cat=X7466
AOBIOUS INC	AOB87176	http://aobious.com/aobious/search?search_query=AOB87176
ApexBio Technology	A3632	https://www.apexbt.com/catalogsearch/result/?q=A3632
ApexBio Technology	A5017	https://www.apexbt.com/catalogsearch/result/?q=A5017
AstaTech	40617	http://astatechinc.com/CPSResult.php?CRNO=40617
AstaTech	61834	http://astatechinc.com/CPSResult.php?CRNO=61834
Axon MedChem	1768	https://www.axonmedchem.com/product/1768
BLD Pharm	BD210719	http://www.bldpharm.com/search/Search.html?keyword=BD210719
BLD Pharm	BD559247	http://www.bldpharm.com/search/Search.html?keyword=BD559247
BOC Sciences	453562-69-1	http://www.bocsci.com/description.asp?cas=453562-69-1
Capot Chemical	22412	https://www.capotchem.com/search.do?q=22412
Cayman Chemical	17671	http://www.caymanchem.com/app/template/Product.vm/catalog/17671
Chem Scene	CS-0028	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0028
Chem Scene	CS-0193	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0193
ChemShuttle	112447	https://www.chemshuttle.com/catalogsearch/result/?q=112447
ChemShuttle	113670	https://www.chemshuttle.com/catalogsearch/result/?q=113670
Combi-Blocks	QJ-0817	http://www.combi-blocks.com/cgi-bin/find.cgi?QJ-0817
Excenen	EX-A453	http://www.excenen.com/searchresultlist.php?id=EX-A453
Excenen	EX-A487	http://www.excenen.com/searchresultlist.php?id=EX-A487
Exclusive Chemistry	2343	http://www.exchemistry.com/chem-catalog/product-2343.html
Hairui	HR105765	http://www.hairuichem.com/en/product/search.do?q=HR105765
Hairui	HR143778	http://www.hairuichem.com/en/product/search.do?q=HR143778
KeyOrganics	AS-16212	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-16212
KeyOrganics	AS-17019	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-17019
Lab Network	LN01299380	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01299380
Lab Seeker	SC-28323	http://www.labseeker.com/search.php?keywords=SC-28323&category=0
LabSeeker	SC-28323	http://www.labseeker.com/search.php?keywords=SC-28323&category=0
Matrix Scientific	132644	http://www.matrixscientific.com/132644.html
Matrix Scientific	147772	http://www.matrixscientific.com/147772.html
MedChem Express	HY-10228	https://www.medchemexpress.com/search.html?q=HY-10228&ft=&fa=&fp=
MedChem Express	HY-10229	https://www.medchemexpress.com/search.html?q=HY-10229&ft=&fa=&fp=
MolPort	MolPort-009-679-440	https://www.molport.com/shop/molecule-link/MolPort-009-679-440
MolPort	MolPort-016-633-170	https://www.molport.com/shop/molecule-link/MolPort-016-633-170
MolPort	MolPort-046-424-798	https://www.molport.com/shop/molecule-link/MolPort-046-424-798
Molnova	M14539	https://www.molnova.com/en/serch-list.html?keywords=M14539
Molnova	M16223	https://www.molnova.com/en/serch-list.html?keywords=M16223
MuseChem	I003594	https://www.musechem.com/product/I003594.html
Ryan Scientific	Motesanib	https://ryansci.com/products?q=Motesanib&list_q=&search_type=exact
Ryan Scientific	TGR5	https://ryansci.com/products?q=TGR5&list_q=&search_type=exact
Selleck Chemicals	S1032	http://www.selleckchem.com/search.html?searchDTO.searchParam=S1032
ShangHai Biochempartner	BCP000220	http://www.biochempartner.com/search_BCP000220
ShangHai Biochempartner	BCP01822	http://www.biochempartner.com/search_BCP01822
ShangHai Biochempartner	BCP01982	http://www.biochempartner.com/search_BCP01982
TargetMol	T2288	https://www.targetmol.com/search?keyword=T2288
TargetMol	T2288L	https://www.targetmol.com/search?keyword=T2288L
Toronto Research Chemicals	A637252	https://www.trc-canada.com/product-detail/?CatNum=A637252
Toronto Research Chemicals	M732500	https://www.trc-canada.com/product-detail/?CatNum=M732500
eMolecules	31507654	https://orderbb.emolecules.com/search/#?query=31507654
eMolecules	32278026	https://orderbb.emolecules.com/search/#?query=32278026
eMolecules	43639386	https://orderbb.emolecules.com/search/#?query=43639386
eMolecules	48669074	https://orderbb.emolecules.com/search/#?query=48669074
eNovation Chemicals	D388281	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D388281&searchbtn.x=0&searchbtn.y=0
eNovation Chemicals	D518764	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D518764&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-3496762093	https://mcule.com/MCULE-3496762093/
mcule	MCULE-4037113225	https://mcule.com/MCULE-4037113225/
mcule	MCULE-9095751100	https://mcule.com/MCULE-9095751100/

PubMed

Title	Date	PubMed
New molecular targeted therapies in thyroid cancer.	2006 Sep	16940797
Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours.	2008 Nov 4	18971935
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	18574557
Novel therapies in breast cancer: what is new from ASCO 2008.	2008 Oct 1	18828924
Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer.	2009 Aug 10	19564535
Targeting RET for thyroid cancer therapy.	2009 Feb 1	19028457
[Advances in the treatment of thyroid cancer in the era of molecularly targeted therapies].	2009 Jan	19211364
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	19118038
In vitro metabolism of the novel, highly selective oral angiogenesis inhibitor motesanib diphosphate in preclinical species and in humans.	2009 Jul	19372226
Pretargeted radioimmunotherapy in the treatment of metastatic medullary thyroid cancer.	2009 Sep	19862356
Present and future evolution of advanced breast cancer therapy.	2010	21050422
Molecular and other novel advances in treatment of metastatic epithelial and medullary thyroid cancers.	2010	20862373
Advances in cellular therapy for the treatment of thyroid cancer.	2010	20671939
Targeting angiogenesis with multitargeted tyrosine kinase inhibitors in the treatment of non-small cell lung cancer.	2010	20427383
Phase II study of motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate.	2010 Apr	19690858
The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro.	2010 Dec 1	20832415
Targeting RET receptor tyrosine kinase activation in cancer.	2010 Dec 15	20930041
Targeting vascular endothelial growth factor receptor in thyroid cancer: the intracellular and extracellular implications.	2010 Feb 1	20103668
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	20028752
Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors.	2010 Jul 15	20633291
Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors.	2010 Jul 15	20507929
Axitinib: The evidence of its potential in the treatment of advanced thyroid cancer.	2010 Jun 15	20694064
Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action?	2010 Mar	20012482
A phase Ib study of AMG 102 in combination with bevacizumab or motesanib in patients with advanced solid tumors.	2010 May 1	20406832
Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors.	2010 May 5	20351338
Development of a modeling framework to simulate efficacy endpoints for motesanib in patients with thyroid cancer.	2010 Nov	20872147
Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by motesanib in thyroid cancer patients.	2010 Nov	20872145
Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer.	2010 Nov	20739388
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010 Nov 24	21095574
Phase 1 study of the investigational, oral angiogenesis inhibitor motesanib in Japanese patients with advanced solid tumors.	2010 Oct	20107802
Telomerase inhibition targets clonogenic multiple myeloma cells through telomere length-dependent and independent mechanisms.	2010 Sep 1	20824134
Safety and pharmacokinetics of motesanib in combination with panitumumab and gemcitabine-Cisplatin in patients with advanced cancer.	2011	21559248
Comprehensive analysis of kinase inhibitor selectivity.	2011 Oct 30	22037378
Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors.	2012 Dec 27	23098265

Patents

Sample Use Guides

In Vivo Use Guide

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

Motesanib (AMG-706) potently inhibited VEGF-induced proliferation of HUVECs with IC50 values of 10 nM

Name

Type

Language

MOTESANIB DIPHOSPHATE

Official Name

English

MOTESANIB PHOSPHATE

Common Name

English

MOTESANIB DIPHOSPHATE [MI]

Common Name

English

3-PYRIDINECARBOXAMIDE, N-(2,3-DIHYDRO-3,3-DIMETHYL-1H-INDOL-6-YL)-2-((4-PYRIDINYLMETHYL)AMINO)-, PHOSPHATE (1:2)

Systematic Name

English

MOTESANIB DIPHOSPHATE [USAN]

Common Name

English

MOTESANIB PHOSPHATE [JAN]

Common Name

English

Motesanib diphosphate [WHO-DD]

Common Name

English

MOTESANIB DIPHOSPHATE [MART.]

Common Name

English

N-(3,3-DIMETHYL-2,3-DIHYDRO-1H-INDOL-6-YL)-2-((PYRIDIN-4-YLMETHYL)AMINO)NICOTINAMIDE BIS(PHOSPHATE)

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1967