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Details

Stereochemistry ACHIRAL
Molecular Formula C20H28N4O2
Molecular Weight 356.4619
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 4
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ROLOFYLLINE

SMILES

CCCN1C2=C(NC(=N2)C34C[C@@H]5CC3C[C@H](C4)C5)C(=O)N(CCC)C1=O

InChI

InChIKey=PJBFVWGQFLYWCB-QUYAXPHCSA-N
InChI=1S/C20H28N4O2/c1-3-5-23-16-15(17(25)24(6-4-2)19(23)26)21-18(22-16)20-10-12-7-13(11-20)9-14(20)8-12/h12-14H,3-11H2,1-2H3,(H,21,22)/t12-,13+,14?,20?

HIDE SMILES / InChI
Molecular Formula C20H28N4O2
Molecular Weight 356.4619
Charge 0
Count
Stereochemistry MIXED
Additional Stereochemistry No
Defined Stereocenters 2 / 4
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Rolofylline is an adenosine A1-receptor antagonist. Plasma adenosine levels are elevated in patients with heart failure and adenosine A1 receptors in the kidney mediate vasoconstriction of afferent arterioles, reabsorption of sodium and water in proximal tubules, and tubuloglomerular feedback in the juxtaglomerular apparatus. Accordingly, inhibition of these receptors would be expected to increase renal blood flow and enhance diuresis. However, rolofylline showed no difference from placebo in the main efficacy end points in Phase III clinical trials for acute heart-failure patients.

CNS Activity

Originator

Approval Year

Unknown
149124
Targets

Targets

Primary TargetPharmacologyConditionPotency
Antagonist
2849
 8.0 nM [Ki]
Antagonist
2849
 673.0 nM [Ki]
Antagonist
2849
 296.0 nM [Ki]
Antagonist
2849
 4390.0 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Phase III
665
ROLOFYLLINE

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
637 nM
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/20027108
30 mg 1 times / day steady-state, intravenous
dose: 30 mg
route of administration: Intravenous
experiment type: STEADY-STATE
co-administered: Midazolam
Midazolam
 ROLOFYLLINE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
3588 nM × h
EXPERIMENT
https://www.ncbi.nlm.nih.gov/pubmed/20027108
30 mg 1 times / day steady-state, intravenous
dose: 30 mg
route of administration: Intravenous
experiment type: STEADY-STATE
co-administered: Midazolam
Midazolam
 ROLOFYLLINE plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
Doses

Doses

DosePopulationAdverse events​
60 mg single, intravenous
Highest studied dose
Dose: 60 mg
Route: intravenous
Route: single
Dose: 60 mg
Sources:
https://pubmed.ncbi.nlm.nih.gov/20027105
healthy, ADULT
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: FASTED
Sources:
https://pubmed.ncbi.nlm.nih.gov/20027105
Sources:
https://pubmed.ncbi.nlm.nih.gov/20027105
30 mg 1 times / day multiple, intravenous
Studied dose
Dose: 30 mg, 1 times / day
Route: intravenous
Route: multiple
Dose: 30 mg, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/22339573
unhealthy, ADULT
Health Status: unhealthy
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Sources:
https://pubmed.ncbi.nlm.nih.gov/22339573
Sources:
https://pubmed.ncbi.nlm.nih.gov/22339573
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG
substrate
1946

OverviewOther

Other InhibitorOther SubstrateOther Inducer
OAT2
153

OAT1
725

OAT3
747

OAT4
150
Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
OAT2
155
 no
OAT4
150
 yes [Ki 20.7 uM]
OAT3
749
 yes [Ki 3.7 uM]
OAT1
730
 yes [Ki 7.82 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
CYP3A4
1946
 major
Sourcing

Sourcing

Vendor/AggregatorIDURL
Princeton BioMolecular Research
PBMR221756
http://www.princetonbio.com/order_online?common_id=PBMR221756
PubMed

PubMed

TitleDatePubMed
The cardiorenal syndrome: a review.
2010-12-28
Therapeutic options for the management of the cardiorenal syndrome.
2010-12-15
Haemodynamic effects of rolofylline in the treatment of patients with heart failure and impaired renal function.
2010-11
Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure.
2010-10-07
Dyspnoea and worsening heart failure in patients with acute heart failure: results from the Pre-RELAX-AHF study.
2010-10
The effects of adenosine A(1) receptor antagonism in patients with acute decompensated heart failure and worsening renal function: the REACH UP study.
2010-09
Gateways to clinical trials.
2010-06
Gateways to clinical trials.
2010-05
Dyspnoea in patients with acute heart failure: an analysis of its clinical course, determinants, and relationship to 60-day outcomes in the PROTECT pilot study.
2010-05
Design and rationale of the PROTECT study: a placebo-controlled randomized study of the selective A1 adenosine receptor antagonist rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function.
2010-01
Physician-determined worsening heart failure: a novel definition for early worsening heart failure in patients hospitalized for acute heart failure--association with signs and symptoms, hospitalization duration, and 60-day outcomes.
2010
The effects of multiple doses of rolofylline on the single-dose pharmacokinetics of midazolam in healthy subjects.
2009-12-23
A single supratherapeutic dose of rolofylline does not prolong the QTcF interval in healthy volunteers.
2009-12-23
HOTLINE III: End of the line for rolofylline?
2009-12
Clinical trials update from the European Society of Cardiology Meeting 2009: AAA, RELY, PROTECT, ACTIVE-I, European CRT survey, German pre-SCD II registry, and MADIT-CRT.
2009-12
Vasodilators in the treatment of acute heart failure: what we know, what we don't.
2009-12
Cardiorenal syndrome.
2009-10-14
Adenosine1 receptor antagonism: a new therapeutic approach for the treatment of decompensated heart failure.
2009-04-23
Rolofylline: a selective adenosine 1 receptor antagonist for the treatment of heart failure.
2009-02
A1 adenosine receptor antagonists, agonists, and allosteric enhancers.
2009
Gateways to clinical trials. July-August 2008.
2008-10-14
The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment.
2008-10
Adenosine A1 antagonists and the cardiorenal syndrome.
2008-06
Clinical trials update from the American College of Cardiology 2008: CARISMA, TRENDS, meta-analysis of Cox-2 studies, HAT, ON-TARGET, HYVET, ACCOMPLISH, MOMENTUM, PROTECT, HORIZON-HF and REVERSE.
2008-06
Gateways to clinical trials.
2008-05
Rolofylline (KW-3902): a new adenosine A1-receptor antagonist for acute congestive heart failure.
2008-03
Role of adenosine antagonism in the cardiorenal syndrome.
2008
The effects of KW-3902, an adenosine A1-receptor antagonist,on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance.
2007-10-16
The effect of KW-3902, an adenosine A1 receptor antagonist, on renal function and renal plasma flow in ambulatory patients with heart failure and renal impairment.
2007-10
Adenosine A2 receptor activation attenuates afferent arteriolar autoregulation during adenosine receptor saturation in rats.
2007-10
Clinical trials update from Heart Rhythm 2007 and Heart Failure 2007: CARISMA, PREPARE, DAVID II, SAVE-PACE, PROTECT and AREA-IN-CHF.
2007-08
The effect of antagonism of adenosine A1 receptor against ischemia and reperfusion injury of the liver.
2007-05-01
JPMorgan 25th annual healthcare conference. Pipelines from NovaCardia, Quark Biotech, Raven Biotechnologies and Serenex.
2007-03
American Heart Association - Scientific Sessions 2006. Developments in cardiovascular-related therapies.
2007-01
Combined effects of carbonic anhydrase inhibitor and adenosine A1 receptor antagonist on hemodynamic and tubular function in the kidney.
2007
Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antagonists.
2006-11-30
Improving potency, selectivity, and water solubility of adenosine A1 receptor antagonists: xanthines modified at position 3 and related pyrimido[1,2,3-cd]purinediones.
2006-08
Clinical trials update from the European Society of Cardiology heart failure meeting: TNT subgroup analysis, darbepoetin alfa, FERRIC-HF and KW-3902.
2006-08
Norbornyllactone-substituted xanthines as adenosine A(1) receptor antagonists.
2006-06-01
Ischemic preconditioning protects post-ischemic renal function in anesthetized dogs: role of adenosine and adenine nucleotides.
2005-07
Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization.
2003-12-19
Evaluation of the carrier potential for the lipid dispersion system with lipophilic compound.
2003-07
Role of adenosine A(1) receptor in angiotensin II- and norepinephrine-induced renal vasoconstriction.
2002-10
Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors.
2002-06
Vasodilator responses to adenosine and hyperemia are mediated by A(1) and A(2) receptors in the cat vascular bed.
2002-06
Role of the lipid emulsion on an injectable formulation of lipophilic KW-3902, a newly synthesized adenosine A1-receptor antagonist.
2002-04
Evidence against a major role of adenosine in oxygen-dependent regulation of erythropoietin in rats.
1997-08
Synthesis and biological evaluation of the enantiomers of the potent and selective A1-adenosine antagonist 1,3-dipropyl-8-[2-(5,6-epoxynorbonyl)]-xanthine.
1997-06-06
Protective effects of KW-3902, a novel adenosine A1-receptor antagonist, against gentamicin-induced acute renal failure in rats.
1994-06
Effects of KW-3902, a novel adenosine A1-receptor antagonist, on cephaloridine-induced acute renal failure in rats.
1994-01
Patents

Patents

EP0415456
1

Sample Use Guides

In Vivo Use Guide
Rolofylline 30 mg once a day, 3 days.
Route of Administration: Intravenous
In Vitro Use Guide
In rat forebrain adenosine A1 receptors labelled with [3H]-cyclohexyladenosine, rolofylline (KW-3902) had a Ki value of 0.19 nM, whereas it showed a Ki value of 170 nM in rat striatal A2A receptors labelled with [3H]-2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoad enosine, indicating 890 fold A1 receptor selectivity versus the A2A receptor. KW-3902 at 10 microM showed no effect on recombinant rat A3 receptors expressed on CHO cells. Saturation studies with [3H]-KW-3902 revealed that it bound with high affinity (Kd = 77 pM) and limited capacity (Bmax = 470 fmol mg-1 of protein) to a single class of recognition sites.
Substance Class Chemical
Created
by admin
on Mon Mar 31 18:14:10 GMT 2025
Edited
by admin
on Mon Mar 31 18:14:10 GMT 2025
Record UNII
7805S5HIHX
Record Status Validated (UNII)
Record Version
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Name Type Language
KW-3902
Preferred Name English
ROLOFYLLINE
INN   USAN   WHO-DD  
USAN   INN  
Official Name English
KW3902
Code English
rolofylline [INN]
Common Name English
Rolofylline [WHO-DD]
Common Name English
MK-7418
Code English
3,7-DIHYDRO-1,3-DIPROPYL-8-(3-TRICYCLO(3.3.1.0(SUP 3,7))NONYL)-1H-PURINE-2,6-DIONE
Systematic Name English
1,3-DIPROPYL-8-(TRICYCLO(3.3.1.0(SUP 3,7))NON-3-YL)-3,7-DIHYDRO-1H-PURINE-2,6-DIONE
Systematic Name English
ROLOFYLLINE [USAN]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C319
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
Code System Code Type Description
EPA CompTox
DTXSID50929292
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
NCI_THESAURUS
C96195
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
WIKIPEDIA
Rolofylline
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
INN
8923
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
USAN
TT-26
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
SMS_ID
100000175772
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
CAS
136199-02-5
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
DRUG BANK
DB12670
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
ChEMBL
CHEMBL2103819
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
FDA UNII
7805S5HIHX
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
PUBCHEM
11948288
Created by admin on Mon Mar 31 18:14:10 GMT 2025 , Edited by admin on Mon Mar 31 18:14:10 GMT 2025
PRIMARY
Related Record Type Details
ADENOSINE RECEPTOR A1
TARGET -> INHIBITOR
OAT-4
TRANSPORTER -> INHIBITOR
Related Record Type Details
Structure of ROLOFYLLINE
ACTIVE MOIETY
NIH
NCATS
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