MOTESANIB

Investigational

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

Structure Search

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)

HIDE SMILES / InChI

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

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 40 Target ID: CHEMBL1868 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=16951187	Inhibitor 8228	2.0 nM [IC50]
Vascular endothelial growth factor receptor 2 102 Target ID: CHEMBL279 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16951187	Inhibitor 8228	3.0 nM [IC50]
Vascular endothelial growth factor receptor 3 40 Target ID: CHEMBL1955 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16951187	Inhibitor 8228	6.0 nM [IC50]
Stem cell growth factor receptor 52 Target ID: CHEMBL1936 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16951187	Inhibitor 8228	8.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Non-small cell lung cancer 201 Sources: http://adisinsight.springer.com/drugs/800011016	Primary	Phase III 663	Unknown Approved Use Unknown
Thyroid cancer 16 Sources: http://adisinsight.springer.com/drugs/800011016	Primary	Phase II 1144	Unknown Approved Use Unknown
Ovarian cancer 152 Sources: http://adisinsight.springer.com/drugs/800011016	Primary	Phase II 1144	Unknown Approved Use Unknown
Colorectal cancer 99 Sources: http://adisinsight.springer.com/drugs/800011016	Primary	Phase I 424	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 1579 substrate 1709	inhibitor 1752	inhibitor 1837 substrate 1193

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 691 MRP1 106 MRP10 2 CYP1A2 1509 P-gp 1437	UGT1A1 418 CYP1A1 348 CYP2B6 660 UGT 187 CYP3A5 391 UGT1A4 347 CYP3A7 110

Drug as perpetrator

Target	Modality	Activity
MRP1 172	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/24937702/	no
MRP10 2	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/24937702/	no
CYP1A2 1673	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/24462920/	weak [Inhibition 50 uM]
CYP2C9 1803	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/24462920/	yes [Inhibition 1 uM]
CYP3A4 1909	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/24462920/	yes [Inhibition 1 uM]
CYP2D6 1875	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/24462920/	yes [Inhibition 50 uM]
BCRP 765	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/24937702/	yes
P-gp 1626	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/24937702/	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
UGT 187	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/18574557/	major
UGT1A4 347	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	major
CYP1A1 348	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	minor
CYP2D6 1193	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	minor
UGT1A1 418	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	minor
CYP3A4 1709	substrate 3326 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 660	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	weak
CYP3A5 391	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/19372226/	weak
CYP3A7 110	substrate 3326 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
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
Pretargeted radioimmunotherapy in the treatment of metastatic medullary thyroid cancer.	2009 Sep	19862356
Present and future evolution of advanced breast cancer therapy.	2010	21050422
Phase II study of motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate.	2010 Apr	19690858
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
Development of a modeling framework to simulate efficacy endpoints for motesanib in patients with thyroid cancer.	2010 Nov	20872147
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010 Nov 24	21095574

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

Substance Class	Chemical Created by `admin` on `Thu Jul 06 00:43:20 UTC 2023` Edited by `admin` on `Thu Jul 06 00:43:20 UTC 2023`
Record UNII	U1JK633AYI
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

MOTESANIB

Official Name

English

AMG-706

Code

English

N-(3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)amino]pyridine-3-carboxamide

Systematic Name

English

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

Systematic Name

English

MOTESANIB [USAN]

Common Name

English

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

Systematic Name

English

AMG 706

Code

English

MOTESANIB [MART.]

Common Name

English

motesanib [INN]

Common Name

English

Motesanib [WHO-DD]

Common Name

English

MOTESANIB [MI]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1967