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Details

Stereochemistry ACHIRAL
Molecular Formula C20H28N4O2
Molecular Weight 356.4627
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ROLOFYLLINE

SMILES

CCCn1c2c(c(=O)n(CCC)c1=O)nc(C34C[C@@]5([H])C[C@]([H])(CC3([H])C5)C4)[nH]2

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 356.4627
Charge 0
Count
Stereochemistry MIXED
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

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.

Approval Year

Targets

Targets

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

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ROLOFYLLINE

Approved Use

Unknown
Doses

Doses

DosePopulationAdverse events​
60 mg single, intravenous
Highest studied dose
Dose: 60 mg
Route: intravenous
Route: single
Dose: 60 mg
Sources: Page: p.14
healthy, ADULT
n = 48
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: FASTED
Population Size: 48
Sources: Page: p.14
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: Page: p.243
unhealthy, ADULT
n = 1356
Health Status: unhealthy
Condition: heart disease
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 1356
Sources: Page: p.243
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG

OverviewOther

Other InhibitorOther SubstrateOther Inducer




Drug as perpetrator​Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
PubMed

PubMed

TitleDatePubMed
Effects of KW-3902, a novel adenosine A1-receptor antagonist, on cephaloridine-induced acute renal failure in rats.
1994 Jan
Protective effects of KW-3902, a novel adenosine A1-receptor antagonist, against gentamicin-induced acute renal failure in rats.
1994 Jun
Evidence against a major role of adenosine in oxygen-dependent regulation of erythropoietin in rats.
1997 Aug
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 Jun 6
Formulation development of a filter-sterilizable lipid emulsion for lipophilic KW-3902, a newly synthesized adenosine A1-receptor antagonist.
2002 Jan
KF24345, an adenosine uptake inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor-alpha production and leukopenia via endogenous adenosine in mice.
2002 Jan
Role of adenosine A(1) receptor in angiotensin II- and norepinephrine-induced renal vasoconstriction.
2002 Oct
Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization.
2003 Dec 19
Evaluation of the carrier potential for the lipid dispersion system with lipophilic compound.
2003 Jul
Ischemic preconditioning protects post-ischemic renal function in anesthetized dogs: role of adenosine and adenine nucleotides.
2005 Jul
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 Aug
Clinical trials update from the European Society of Cardiology heart failure meeting: TNT subgroup analysis, darbepoetin alfa, FERRIC-HF and KW-3902.
2006 Aug
Norbornyllactone-substituted xanthines as adenosine A(1) receptor antagonists.
2006 Jun 1
Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antagonists.
2006 Nov 30
Combined effects of carbonic anhydrase inhibitor and adenosine A1 receptor antagonist on hemodynamic and tubular function in the kidney.
2007
Clinical trials update from Heart Rhythm 2007 and Heart Failure 2007: CARISMA, PREPARE, DAVID II, SAVE-PACE, PROTECT and AREA-IN-CHF.
2007 Aug
American Heart Association - Scientific Sessions 2006. Developments in cardiovascular-related therapies.
2007 Jan
JPMorgan 25th annual healthcare conference. Pipelines from NovaCardia, Quark Biotech, Raven Biotechnologies and Serenex.
2007 Mar
The effect of antagonism of adenosine A1 receptor against ischemia and reperfusion injury of the liver.
2007 May 1
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 Oct
Adenosine A2 receptor activation attenuates afferent arteriolar autoregulation during adenosine receptor saturation in rats.
2007 Oct
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 Oct 16
Gateways to clinical trials. July-August 2008.
2008 Jul-Aug
Adenosine A1 antagonists and the cardiorenal syndrome.
2008 Jun
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 Jun
Rolofylline (KW-3902): a new adenosine A1-receptor antagonist for acute congestive heart failure.
2008 Mar
Gateways to clinical trials.
2008 May
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 Oct
Role of adenosine antagonism in the cardiorenal syndrome.
2008 Winter
A1 adenosine receptor antagonists, agonists, and allosteric enhancers.
2009
HOTLINE III: End of the line for rolofylline?
2009 Dec
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 Dec
Vasodilators in the treatment of acute heart failure: what we know, what we don't.
2009 Dec
Rolofylline: a selective adenosine 1 receptor antagonist for the treatment of heart failure.
2009 Feb
Adenosine1 receptor antagonism: a new therapeutic approach for the treatment of decompensated heart failure.
2009 May-Jun
Cardiorenal syndrome.
2009 Oct 14
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
Therapeutic options for the management of the cardiorenal syndrome.
2010 Dec 15
The cardiorenal syndrome: a review.
2010 Dec 28
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 Jan
The effects of multiple doses of rolofylline on the single-dose pharmacokinetics of midazolam in healthy subjects.
2010 Jan-Feb
A single supratherapeutic dose of rolofylline does not prolong the QTcF interval in healthy volunteers.
2010 Jan-Feb
Gateways to clinical trials.
2010 Jun
Gateways to clinical trials.
2010 May
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 May
Haemodynamic effects of rolofylline in the treatment of patients with heart failure and impaired renal function.
2010 Nov
Dyspnoea and worsening heart failure in patients with acute heart failure: results from the Pre-RELAX-AHF study.
2010 Oct
Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure.
2010 Oct 7
The effects of adenosine A(1) receptor antagonism in patients with acute decompensated heart failure and worsening renal function: the REACH UP study.
2010 Sep
Patents

Patents

Sample Use Guides

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 Sat Jun 26 05:49:52 UTC 2021
Edited
by admin
on Sat Jun 26 05:49:52 UTC 2021
Record UNII
7805S5HIHX
Record Status Validated (UNII)
Record Version
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Name Type Language
ROLOFYLLINE
INN   USAN   WHO-DD  
USAN   INN  
Official Name English
KW 3902
Code English
ROLOFYLLINE [INN]
Common Name English
KW-3902
Code 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 Sat Jun 26 05:49:52 UTC 2021 , Edited by admin on Sat Jun 26 05:49:52 UTC 2021
Code System Code Type Description
NCI_THESAURUS
C96195
Created by admin on Sat Jun 26 05:49:52 UTC 2021 , Edited by admin on Sat Jun 26 05:49:52 UTC 2021
PRIMARY
INN
8923
Created by admin on Sat Jun 26 05:49:52 UTC 2021 , Edited by admin on Sat Jun 26 05:49:52 UTC 2021
PRIMARY
CAS
136199-02-5
Created by admin on Sat Jun 26 05:49:52 UTC 2021 , Edited by admin on Sat Jun 26 05:49:52 UTC 2021
PRIMARY
DRUG BANK
DB12670
Created by admin on Sat Jun 26 05:49:52 UTC 2021 , Edited by admin on Sat Jun 26 05:49:52 UTC 2021
PRIMARY
ChEMBL
CHEMBL2103819
Created by admin on Sat Jun 26 05:49:52 UTC 2021 , Edited by admin on Sat Jun 26 05:49:52 UTC 2021
PRIMARY
FDA UNII
7805S5HIHX
Created by admin on Sat Jun 26 05:49:52 UTC 2021 , Edited by admin on Sat Jun 26 05:49:52 UTC 2021
PRIMARY
PUBCHEM
11948288
Created by admin on Sat Jun 26 05:49:52 UTC 2021 , Edited by admin on Sat Jun 26 05:49:52 UTC 2021
PRIMARY
Related Record Type Details
TRANSPORTER -> INHIBITOR
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ACTIVE MOIETY