AMG-517

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H13F3N4O2S
Molecular Weight	430.403
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(=O)NC1=NC2=C(OC3=NC=NC(=C3)C4=CC=C(C=C4)C(F)(F)F)C=CC=C2S1

InChI

InChIKey=YUTIXVXZQIQWGY-UHFFFAOYSA-N

InChI=1S/C20H13F3N4O2S/c1-11(28)26-19-27-18-15(3-2-4-16(18)30-19)29-17-9-14(24-10-25-17)12-5-7-13(8-6-12)20(21,22)23/h2-10H,1H3,(H,26,27,28)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17652633 | https://www.ncbi.nlm.nih.gov/pubmed/18337008 | http://adisinsight.springer.com/drugs/800021804
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/18386885

AMG-517, a potent and selective vanilloid receptor (VR1) antagonist, was in clinical trials with Amgen for the treatment of pain. AMG 517 inhibits CAP- (500 nM), acid- (pH 5.0), or heat-(45 °C) induced 45Ca2+ influx into human TRPV1-expressing CHO Cells with IC50 of 0.76 nM, 0.62 nM and 1.3 nM. AMG-517 blocks capsaicin-, proton-, and heat-induced inward currents in TRPV1-expressing cells similarly. AMG-517 inhibits native TRPV1 activation by capsaicin in rat dorsal root ganglion neurons with an IC50 value of 0.68 nM. Oral administration of AMG-517 produces a dose-dependent increase in plasma concentrations, it also produces a dose-dependent decrease in the number of flinches induced by capsaicin treatment. The minimally effective dose (MED), based on a statistically significant difference in number of flinches from the vehicle versus capsaicin-administered group, is 0.3 mg/kg for AMG 517. The corresponding plasma concentrations are 90 to 100 ng/mL for AMG-517. AMG-517 (3 mg/kg) exhibits significant reductions in capsaicin-induced flinch up to 24 h after dosing. AMG 517 blocks thermal hyperalgesia in CFA model of pain. Unfortunately, clinical studies of AMG-517 were discontinued due to the hyperthermia observed after exposure to single and multiple doses.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Vanilloid receptor 53 Target ID: CHEMBL4794 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17652633 \| https://www.ncbi.nlm.nih.gov/pubmed/18386885	Antagonist 2849		0.6 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pain 619 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18386885 http://adisinsight.springer.com/drugs/800021804	Palliative		Phase I 438	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
211 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18337008/	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:	AMG-517 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
105 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18337008/	5 mg 1 times / day multiple, oral dose: 5 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMG-517 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
45.2 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18337008/	2 mg 1 times / day multiple, oral dose: 2 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMG-517 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
199 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18337008/	10 mg 1 times / day multiple, oral dose: 10 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMG-517 plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
10 mg 1 times / day multiple, oral Highest studied dose Dose: 10 mg, 1 times / day Route: oral Route: multiple Dose: 10 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18337008	healthy Health Status: healthy Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/18337008	Other AEs: Hyperthermia... Other AEs: Hyperthermia Sources: https://pubmed.ncbi.nlm.nih.gov/18337008
25 mg single, oral Highest studied dose Dose: 25 mg Route: oral Route: single Dose: 25 mg Sources: https://pubmed.ncbi.nlm.nih.gov/18337008	healthy Health Status: healthy Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/18337008	Other AEs: Hyperthermia... Other AEs: Hyperthermia (1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/18337008

AEs

AE	Significance	Dose	Population
Hyperthermia		10 mg 1 times / day multiple, oral Highest studied dose Dose: 10 mg, 1 times / day Route: oral Route: multiple Dose: 10 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/18337008	healthy Health Status: healthy Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/18337008
Hyperthermia	1 pt	25 mg single, oral Highest studied dose Dose: 25 mg Route: oral Route: single Dose: 25 mg Sources: https://pubmed.ncbi.nlm.nih.gov/18337008	healthy Health Status: healthy Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/18337008

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P00FCFY	https://www.1pchem.com/search?query=1P00FCFY
AK Scientific	2210AH	https://aksci.com/item_detail.php?cat=2210AH
AOBIOUS INC	AOB87374	http://aobious.com/aobious/search?search_query=AOB87374
ApexBio Technology	A1174	https://www.apexbt.com/catalogsearch/result/?q=A1174
AstaTech	43307	http://astatechinc.com/CPSResult.php?CRNO=43307
BLD Pharm	BD370208	http://www.bldpharm.com/search/Search.html?keyword=BD370208
BOC Sciences	659730-32-2	http://www.bocsci.com/description.asp?cas=659730-32-2
Chem Scene	CS-0980	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0980
ChemShuttle	111863	https://www.chemshuttle.com/catalogsearch/result/?q=111863
eMolecules	35999379	https://orderbb.emolecules.com/search/#?query=35999379
eNovation Chemicals	D372554	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D372554&searchbtn.x=0&searchbtn.y=0
Excenen	EX-A2915	http://www.excenen.com/searchresultlist.php?id=EX-A2915
KeyOrganics	BD-0082	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=BD-0082
Matrix Scientific	147208	http://www.matrixscientific.com/147208.html
mcule	MCULE-6823978511	https://mcule.com/MCULE-6823978511/
MedChem Express	HY-10634	https://www.medchemexpress.com/search.html?q=HY-10634&ft=&fa=&fp=
Molnova	M15510	https://www.molnova.com/en/serch-list.html?keywords=M15510
MolPort	MolPort-009-194-112	https://www.molport.com/shop/molecule-link/MolPort-009-194-112
MuseChem	I004486	https://www.musechem.com/product/I004486.html
Selleck Chemicals	S7115	http://www.selleckchem.com/search.html?searchDTO.searchParam=S7115
ShangHai Biochempartner	BCP000817	http://www.biochempartner.com/search_BCP000817
ShangHai Biochempartner	BCP07380	http://www.biochempartner.com/search_BCP07380
TargetMol	T6379	https://www.targetmol.com/search?keyword=T6379

PubMed

Title	Date	PubMed
Improved pharmacokinetics of AMG 517 through co-crystallization. Part 1: comparison of two acids with corresponding amide co-crystals.	2010-09	20665842
Discovery of novel 6,6-heterocycles as transient receptor potential vanilloid (TRPV1) antagonists.	2010-04-22	20307063
Manufacture of pharmaceutical co-crystals using twin screw extrusion: a solvent-less and scalable process.	2010-04	19774652
Analgesic potential of TRPV1 antagonists.	2009-08-01	19481638
Enhanced bioavailability of a poorly soluble VR1 antagonist using an amorphous solid dispersion approach: a case study.	2009-05-13	19434920
Characterization and optimization of AMG 517 supersaturatable self-emulsifying drug delivery system (S-SEDDS) for improved oral absorption.	2009-02	18543293
Substituted aryl pyrimidines as potent and soluble TRPV1 antagonists.	2008-09-15	18722118
The co-crystal approach to improve the exposure of a water-insoluble compound: AMG 517 sorbic acid co-crystal characterization and pharmacokinetics.	2008-09	18214948
On the thermoregulatory perils of TRPV1 antagonism.	2008-05	18359567
Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans.	2008-05	18337008
4-Aminopyrimidine tetrahydronaphthols: a series of novel vanilloid receptor-1 antagonists with improved solubility properties.	2008-03-15	18299195
Trisubstituted pyrimidines as transient receptor potential vanilloid 1 (TRPV1) antagonists with improved solubility.	2007-12-01	17937985
Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade.	2007-10	17652633
Novel vanilloid receptor-1 antagonists: 3. The identification of a second-generation clinical candidate with improved physicochemical and pharmacokinetic properties.	2007-07-26	17585751
Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate.	2007-07-26	17585750

Patents

Sample Use Guides

In Vivo Use Guide

Healthy adults were randomized to receive a single daily dose over 7 days of either placebo or 2, 5 or 10 mg AMG -517

Route of Administration: Oral

In Vitro Use Guide

AMG-517 inhibits CAP- (500 nM), acid- (pH 5.0), or heat-(45 °C) induced 45Ca2+ influx into human TRPV1-expressing CHO Cells with IC50 of 0.76 nM, 0.62 nM and 1.3 nM.

Name

Type

Language

ACETAMIDE, N-(4-((6-(4-(TRIFLUOROMETHYL)PHENYL)-4-PYRIMIDINYL)OXY)-2-BENZOTHIAZOLYL)-

Preferred Name

English

AMG-517

Common Name

English

Code System Code Type Description

SMS_ID

300000042377