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Details

Stereochemistry ABSOLUTE
Molecular Formula C32H28F3N5O4
Molecular Weight 603.5922
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of AMG-487

SMILES

CCOc1ccc(cc1)-n2c([C@@]([H])(C)N(Cc3cccnc3)C(=O)Cc4ccc(cc4)OC(F)(F)F)nc5c(cccn5)c2=O

InChI

InChIKey=WQTKNBPCJKRYPA-OAQYLSRUSA-N
InChI=1S/C32H28F3N5O4/c1-3-43-25-14-10-24(11-15-25)40-30(38-29-27(31(40)42)7-5-17-37-29)21(2)39(20-23-6-4-16-36-19-23)28(41)18-22-8-12-26(13-9-22)44-32(33,34)35/h4-17,19,21H,3,18,20H2,1-2H3/t21-/m1/s1

HIDE SMILES / InChI

Molecular Formula C32H28F3N5O4
Molecular Weight 603.5922
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment:: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/19088267

AMG-487 is a potent and selective orally bioavailable chemokine (C-X-C motif) receptor 3 (CXCR3) antagonist that displays dose- and time-dependent pharmacokinetics in human subjects after multiple oral dosing. AMG-487 is an 8-azaquinazolinone, it can prevent the chemokines I-IP-10 and I-ITAC from binding to CXCR3. The preclinical properties of AMG487 has been extensively studied. The compound displays a greater than 1000-fold selectivity for CXCR3 versus a panel of other receptors, including 11 chemokine receptors. The safety profile of AMG487, as assessed by various genotoxicity and cardiotoxicity assays, revealed no major concerns. The ability of AMG487 to inhibit inflammatory cell migration in vivo was confirmed in a mouse model of bleomycin-induced cellular recruitment, where AMG487 significantly reduced infiltration of macrophages and lymphocytes into the lungs in CXCR3-KO mice. In a mouse model for idiopathic pneumonia syndrome (IPS), AMG487 reduced recruitment of donor T cells to the lung after allogeneic stem cell transplantation, leading to improved survival rates. Likewise, reductions in inflammation, pannus formation, and cartilage damage were observed upon administering AMG487. The preclinical studies convincingly paved the way for clinical studies on two inflammation-related diseases: psoriasis and rheumatoid arthritis. In 2003, results of a Phase I trial on AMG487 were disclosed. The compound was assessed for safety and pharmacokinetics in 30 healthy males in a randomised, double blind, placebo-controlled dose-escalation study. Generally, the compound was well tolerated and adverse events were mild to moderate. Disappointingly, no significant differences in the endpoints (psoriasis severity index or physician global assessment scores) were seen between patient groups. AMG-487 progressed to Phase II clinical trials but has been withdrawn because of lack of efficacy.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
8.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
0.052 μM
25 mg 1 times / day steady-state, oral
dose: 25 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
AMG-487 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
2.8 μM
250 mg 1 times / day multiple, oral
dose: 250 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
AMG-487 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
0.43 μM
100 mg 1 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
AMG-487 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
0.11 μM
25 mg 1 times / day steady-state, oral
dose: 25 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
AMG-487 METABOLITE M1 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
1.3 μM
250 mg 1 times / day multiple, oral
dose: 250 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
AMG-487 METABOLITE M1 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
0.62 μM
100 mg 1 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
AMG-487 METABOLITE M1 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
0.28 μM × h
25 mg 1 times / day steady-state, oral
dose: 25 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
AMG-487 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
27 μM × h
250 mg 1 times / day multiple, oral
dose: 250 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
AMG-487 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
3.3 μM × h
100 mg 1 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
AMG-487 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
0.52 μM × h
25 mg 1 times / day steady-state, oral
dose: 25 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
AMG-487 METABOLITE M1 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
15 μM × h
250 mg 1 times / day multiple, oral
dose: 250 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
AMG-487 METABOLITE M1 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
3.6 μM × h
100 mg 1 times / day multiple, oral
dose: 100 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
AMG-487 METABOLITE M1 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
9.7 h
25 mg 1 times / day steady-state, oral
dose: 25 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
AMG-487 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
9 h
25 mg 1 times / day steady-state, oral
dose: 25 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
AMG-487 METABOLITE M1 plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
Doses

Doses

DosePopulationAdverse events​
1100 mg 1 times / day single, oral (total daily dose)
Highest studied dose
Dose: 1100 mg, 1 times / day
Route: oral
Route: single
Dose: 1100 mg, 1 times / day
Sources:
healthy, ADULT
Health Status: healthy
Age Group: ADULT
Sex: unknown
Food Status: UNKNOWN
Sources:
Other AEs: Adverse drug reaction...
Other AEs:
Adverse drug reaction (moderate)
Sources:
200 mg 1 times / day multiple, oral (unknown)
Highest studied dose
Dose: 200 mg, 1 times / day
Route: oral
Route: multiple
Dose: 200 mg, 1 times / day
Sources:
unhealthy, ADULT
Health Status: unhealthy
Condition: psoriasis
Age Group: ADULT
Sex: unknown
Food Status: UNKNOWN
Sources:
AEs

AEs

AESignificanceDosePopulation
Adverse drug reaction moderate
1100 mg 1 times / day single, oral (total daily dose)
Highest studied dose
Dose: 1100 mg, 1 times / day
Route: oral
Route: single
Dose: 1100 mg, 1 times / day
Sources:
healthy, ADULT
Health Status: healthy
Age Group: ADULT
Sex: unknown
Food Status: UNKNOWN
Sources:
Overview

OverviewOther

Other InhibitorOther SubstrateOther Inducer









Drug as perpetrator​Drug as victim
PubMed

PubMed

TitleDatePubMed
An inhibitory metabolite leads to dose- and time-dependent pharmacokinetics of (R)-N-{1-[3-(4-ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxy-phenyl)-acetamide (AMG 487) in human subjects after multiple dosing.
2009 Mar
Patents

Sample Use Guides

In a Phase IIa trial, patients suffering from psoriasis received 50 or 200 mg of AMG-487 or placebo orally once a day for 28 days.
Route of Administration: Oral
AMG-487 significantly reduced DA FLS invasion in a dose-dependent manner by as much as 77% at 10uM concentrations. AMG-487 (100 uM) also significantly reduced invasion of FLS obtained from RA patients by 58%
Substance Class Chemical
Created
by admin
on Sat Jun 26 00:40:26 UTC 2021
Edited
by admin
on Sat Jun 26 00:40:26 UTC 2021
Record UNII
355CGR2CBL
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
AMG-487
Common Name English
BENZENEACETAMIDE, N-((1R)-1-(3-(4-ETHOXYPHENYL)-3,4-DIHYDRO-4-OXOPYRIDO(2,3-D)PYRIMIDIN-2-YL)ETHYL)-N-(3-PYRIDINYLMETHYL)-4-(TRIFLUOROMETHOXY)-
Systematic Name English
Code System Code Type Description
FDA UNII
355CGR2CBL
Created by admin on Sat Jun 26 00:40:26 UTC 2021 , Edited by admin on Sat Jun 26 00:40:26 UTC 2021
PRIMARY
CAS
473719-41-4
Created by admin on Sat Jun 26 00:40:26 UTC 2021 , Edited by admin on Sat Jun 26 00:40:26 UTC 2021
PRIMARY
PUBCHEM
24957182
Created by admin on Sat Jun 26 00:40:26 UTC 2021 , Edited by admin on Sat Jun 26 00:40:26 UTC 2021
PRIMARY
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