U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C20H24N4O4
Molecular Weight 384.4297
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of ISTRADEFYLLINE

SMILES

CCn1c2c(c(=O)n(CC)c1=O)n(C)c(/C(/[H])=C(\[H])/c3ccc(c(c3)OC)OC)n2

InChI

InChIKey=IQVRBWUUXZMOPW-PKNBQFBNSA-N
InChI=1S/C20H24N4O4/c1-6-23-18-17(19(25)24(7-2)20(23)26)22(3)16(21-18)11-9-13-8-10-14(27-4)15(12-13)28-5/h8-12H,6-7H2,1-5H3/b11-9+

HIDE SMILES / InChI

Molecular Formula C20H24N4O4
Molecular Weight 384.4297
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Istradefylline is a first-in-class adenosine A2A receptor antagonist antiparkinsonian agent and has been marketed as the brand name NOURIAST® in Japan since May 30, 2013. NOURIAST is indicated for the improvement of wearing-off phenomena in patients with Parkinson’s disease on concomitant treatment with levodopa-containing products.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
12.0 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
NOURIAST

Approved Use

Improvement of wearing-off phenomena in patients with Parkinson’s disease on concomitant treatment with levodopa-containing products.

Launch Date

1.36987201E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
230.9 ng/mL
20 mg 1 times / day steady-state, oral
dose: 20 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
ISTRADEFYLLINE unknown
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
3249 ng × h/mL
20 mg 1 times / day steady-state, oral
dose: 20 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
ISTRADEFYLLINE unknown
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
72.1 h
20 mg 1 times / day steady-state, oral
dose: 20 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
ISTRADEFYLLINE unknown
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources:
unhealthy, 65 years (range: 33 - 84 years)
n = 124
Health Status: unhealthy
Age Group: 65 years (range: 33 - 84 years)
Sex: M+F
Population Size: 124
Sources:
Disc. AE: Dyskinesia...
AEs leading to
discontinuation/dose reduction:
Dyskinesia (6%)
Sources:
120 mg 1 times / day steady, oral
Highest studied dose
Dose: 120 mg, 1 times / day
Route: oral
Route: steady
Dose: 120 mg, 1 times / day
Sources: Page: p. 53
unhealthy
n = 142
Health Status: unhealthy
Population Size: 142
Sources: Page: p. 53
Other AEs: Chest pain...
300 mg single, oral
Highest studied dose
Dose: 300 mg
Route: oral
Route: single
Dose: 300 mg
Sources: Page: p. 16
unhealthy
Health Status: unhealthy
Condition: Parkinson’s disease
Sources: Page: p. 16
120 mg single, oral
Overdose
Dose: 120 mg
Route: oral
Route: single
Dose: 120 mg
Sources:
unhealthy
n = 1
Health Status: unhealthy
Population Size: 1
Sources:
Other AEs: Hallucinations, Agitation...
Other AEs:
Hallucinations
Agitation
Dyskinesia
Sources:
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: p. 38
unhealthy
n = 378
Health Status: unhealthy
Population Size: 378
Sources: Page: p. 38
Disc. AE: Visual hallucinations, Hallucination olfactory...
Other AEs: Auditory hallucinations...
AEs leading to
discontinuation/dose reduction:
Visual hallucinations (1%)
Hallucination olfactory (1%)
Somatic hallucination (1%)
Other AEs:
Auditory hallucinations (1%)
Sources: Page: p. 38
AEs

AEs

AESignificanceDosePopulation
Dyskinesia 6%
Disc. AE
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources:
unhealthy, 65 years (range: 33 - 84 years)
n = 124
Health Status: unhealthy
Age Group: 65 years (range: 33 - 84 years)
Sex: M+F
Population Size: 124
Sources:
Chest pain 0.7%
120 mg 1 times / day steady, oral
Highest studied dose
Dose: 120 mg, 1 times / day
Route: oral
Route: steady
Dose: 120 mg, 1 times / day
Sources: Page: p. 53
unhealthy
n = 142
Health Status: unhealthy
Population Size: 142
Sources: Page: p. 53
Agitation
120 mg single, oral
Overdose
Dose: 120 mg
Route: oral
Route: single
Dose: 120 mg
Sources:
unhealthy
n = 1
Health Status: unhealthy
Population Size: 1
Sources:
Dyskinesia
120 mg single, oral
Overdose
Dose: 120 mg
Route: oral
Route: single
Dose: 120 mg
Sources:
unhealthy
n = 1
Health Status: unhealthy
Population Size: 1
Sources:
Hallucinations
120 mg single, oral
Overdose
Dose: 120 mg
Route: oral
Route: single
Dose: 120 mg
Sources:
unhealthy
n = 1
Health Status: unhealthy
Population Size: 1
Sources:
Auditory hallucinations 1%
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: p. 38
unhealthy
n = 378
Health Status: unhealthy
Population Size: 378
Sources: Page: p. 38
Hallucination olfactory 1%
Disc. AE
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: p. 38
unhealthy
n = 378
Health Status: unhealthy
Population Size: 378
Sources: Page: p. 38
Somatic hallucination 1%
Disc. AE
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: p. 38
unhealthy
n = 378
Health Status: unhealthy
Population Size: 378
Sources: Page: p. 38
Visual hallucinations 1%
Disc. AE
40 mg 1 times / day steady, oral
Recommended
Dose: 40 mg, 1 times / day
Route: oral
Route: steady
Dose: 40 mg, 1 times / day
Sources: Page: p. 38
unhealthy
n = 378
Health Status: unhealthy
Population Size: 378
Sources: Page: p. 38
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
likely
likely
likely
likely
likely
likely
likely
no
not significant [IC50 >100 uM]
not significant [IC50 >100 uM]
not significant [IC50 >100 uM]
not significant [IC50 >100 uM]
unlikely
unlikely
unlikely
weak [IC50 1.74 uM]
weak (co-administration study)
Comment: administered with digoxin (substrate); digoxin exposures increased by 33% (Cmax) and 21% (AUC0-inf)
Page: 11;121
yes [IC50 2.9 uM]
yes (co-administration study)
Comment: administered with midazolam (substrate): doses of 80 mg/day of istradefylline resulted in 1.6-fold (Cmax) and 2.4-fold (AUC0-inf) increase in midazolam exposures; administered with atorvastatin (substrate): doses of 40 mg/day of istradefylline resulted in 1.5-fold (Cmax and AUC0-inf) increase in atorvastatin exposures
Page: 11;145
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
yes (co-administration study)
Comment: administered with ketoconazole (inhibitor); the exposures of istradefylline increased by 2.5-fold for AUC0-inf while Cmax was not affected; administered with rifampin: the exposures of istradefylline decreased by 45% and 81% for Cmax and AUC, respectively;
Page: 11,22
minor
minor
minor
minor
minor
no
no
no
yes
yes
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP.
1999 Nov
Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys.
2000 Apr
Adenosine A(2a) receptor antagonists: potential therapeutic and neuroprotective effects in Parkinson's disease.
2001 Nov
Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia.
2003 Mar
A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson's disease.
2003 Nov
Pharmacological validation of a mouse model of l-DOPA-induced dyskinesia.
2005 Jul
Forebrain adenosine A2A receptors contribute to L-3,4-dihydroxyphenylalanine-induced dyskinesia in hemiparkinsonian mice.
2006 Dec 27
2,6,8-trisubstituted 1-deazapurines as adenosine receptor antagonists.
2007 Feb 22
Tremorolytic effects of adenosine A2A antagonists: implications for parkinsonism.
2008 May 1
The effects of adenosine A2A receptor antagonists on haloperidol-induced movement disorders in primates.
2008 Oct
Dual inhibition of monoamine oxidase B and antagonism of the adenosine A(2A) receptor by (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues.
2008 Sep 15
Effects of the adenosine A 2A antagonist KW 6002 (istradefylline) on pimozide-induced oral tremor and striatal c-Fos expression: comparisons with the muscarinic antagonist tropicamide.
2009 Sep 29
Discovery of phosphoric acid mono-{2-[(E/Z)-4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-benzoylimino]-thiazol-3-ylmethyl} ester (Lu AA47070): a phosphonooxymethylene prodrug of a potent and selective hA(2A) receptor antagonist.
2011 Feb 10
International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update.
2011 Mar
Patents

Sample Use Guides

To be administered concomitantly with levodopa-containing products. The usual adult dosage of istradefylline is 20 mg orally administered once daily. According to symptoms, 40 mg of istradefylline can be orally administered once daily.
Route of Administration: Oral
The binding kinetics of istradefylline to the human A2A receptor were investigated using 1 nmol/L of [3H]-istradefylline binding to the human A2A receptor.
Substance Class Chemical
Created
by admin
on Sat Jun 26 10:56:36 UTC 2021
Edited
by admin
on Sat Jun 26 10:56:36 UTC 2021
Record UNII
2GZ0LIK7T4
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ISTRADEFYLLINE
DASH   INN   JAN   MI   USAN   WHO-DD  
INN   USAN  
Official Name English
KW-6002
Code English
(E)-8-(3,4-DIMETHOXYSTYRYL)-1,3-DIETHYL-7-METHYL-3,7-DIHYDRO-1H-PURINE-2,6-DIONE
Systematic Name English
8-((1E)-2-(3,4-DIMETHOXYPHENYL)ETHENYL)-1,3-DIETHYL-7-METHYL-3,7-DIHYDRO-1H-PURINE-2,6-DIONE
Systematic Name English
1H-PURINE-2,6-DIONE, 8-((1E)-2-(3,4-DIMETHOXYPHENYL)ETHENYL)-1,3-DIETHYL-3,7-DIHYDRO-7-METHYL-
Systematic Name English
ISTRADEFYLLINE [USAN]
Common Name English
ISTRADEFYLLINE [MI]
Common Name English
ISTRADEFYLLINE [JAN]
Common Name English
ISTRADEFYLLINE [INN]
Common Name English
NOURIANZ
Brand Name English
ISTRADEFYLLINE [ORANGE BOOK]
Common Name English
NOURIAST
Brand Name English
ISTRADEFYLLINE [WHO-DD]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C38149
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
Code System Code Type Description
MERCK INDEX
M6559
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY Merck Index
JAPANESE REVIEW
NOURIAST
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY APPROVED MARCH 2013
PUBCHEM
5311037
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
RXCUI
2199015
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
INN
8387
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
DRUG BANK
DB11757
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
ChEMBL
CHEMBL431770
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
CAS
155270-99-8
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
EPA CompTox
155270-99-8
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
WIKIPEDIA
ISTRADEFYLLINE
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
FDA UNII
2GZ0LIK7T4
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
MESH
C111599
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
NCI_THESAURUS
C73268
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
EVMPD
SUB126676
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
DRUG CENTRAL
4882
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
IUPHAR
5608
Created by admin on Sat Jun 26 10:56:37 UTC 2021 , Edited by admin on Sat Jun 26 10:56:37 UTC 2021
PRIMARY
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