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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
139594
Targets

Targets

Primary TargetPharmacologyConditionPotency
Antagonist
2778
 8.0 nM [Ki]
Antagonist
2778
 673.0 nM [Ki]
Antagonist
2778
 296.0 nM [Ki]
Antagonist
2778
 4390.0 nM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Phase III
656
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:
https://pubmed.ncbi.nlm.nih.gov/20027105
Page: p.14
healthy, ADULT
n = 48
Health Status: healthy
Age Group: ADULT
Sex: M+F
Food Status: FASTED
Population Size: 48
Sources:
https://pubmed.ncbi.nlm.nih.gov/20027105
Page: p.14
Sources:
https://pubmed.ncbi.nlm.nih.gov/20027105
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:
https://pubmed.ncbi.nlm.nih.gov/22339573
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:
https://pubmed.ncbi.nlm.nih.gov/22339573
Page: p.243
Sources:
https://pubmed.ncbi.nlm.nih.gov/22339573
Page: p.243
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG
substrate
1737

OverviewOther

Other InhibitorOther SubstrateOther Inducer
OAT2
145

OAT1
599

OAT3
642

OAT4
146
Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
OAT2
147
 no
OAT4
146
 yes [Ki 20.7 uM]
OAT3
644
 yes [Ki 3.7 uM]
OAT1
603
 yes [Ki 7.82 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
CYP3A4
1737
 major
Sourcing

Sourcing

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

PubMed

TitleDatePubMed
Effects of KW-3902, a novel adenosine A1-receptor antagonist, on cephaloridine-induced acute renal failure in rats.
1994 Jan
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
The selective adenosine A1 receptor antagonist KW-3902 prevents radiocontrast media-induced nephropathy in rats with chronic nitric oxide deficiency.
2001 Feb 23
Interactions of adenosine A1 and A2a receptors on renal microvascular reactivity.
2001 Mar
Adenosine A1 receptor antagonist prolongs survival in the hypoxic rat.
2001 Sep
Role of the lipid emulsion on an injectable formulation of lipophilic KW-3902, a newly synthesized adenosine A1-receptor antagonist.
2002 Apr
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
Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors.
2002 Jun
Vasodilator responses to adenosine and hyperemia are mediated by A(1) and A(2) receptors in the cat vascular bed.
2002 Jun
Role of adenosine A(1) receptor in angiotensin II- and norepinephrine-induced renal vasoconstriction.
2002 Oct
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
JPMorgan 25th annual healthcare conference. Pipelines from NovaCardia, Quark Biotech, Raven Biotechnologies and Serenex.
2007 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
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
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
Haemodynamic effects of rolofylline in the treatment of patients with heart failure and impaired renal function.
2010 Nov
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 Fri Dec 15 15:56:48 GMT 2023
Edited
by admin
on Fri Dec 15 15:56:48 GMT 2023
Record UNII
7805S5HIHX
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ROLOFYLLINE
INN   USAN   WHO-DD  
USAN   INN  
Official Name English
KW3902
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 Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
Code System Code Type Description
EPA CompTox
DTXSID50929292
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
NCI_THESAURUS
C96195
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
WIKIPEDIA
Rolofylline
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
INN
8923
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
USAN
TT-26
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
SMS_ID
100000175772
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
CAS
136199-02-5
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
DRUG BANK
DB12670
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
ChEMBL
CHEMBL2103819
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
FDA UNII
7805S5HIHX
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
PUBCHEM
11948288
Created by admin on Fri Dec 15 15:56:48 GMT 2023 , Edited by admin on Fri Dec 15 15:56:48 GMT 2023
PRIMARY
Related Record Type Details
ADENOSINE RECEPTOR A1
TARGET -> INHIBITOR
OAT-4
TRANSPORTER -> INHIBITOR
Related Record Type Details
Structure of ROLOFYLLINE
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