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
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?
| 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 |
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.
Originator
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL226 |
8.0 nM [Ki] | ||
Target ID: CHEMBL251 |
673.0 nM [Ki] | ||
Target ID: CHEMBL255 |
296.0 nM [Ki] | ||
Target ID: CHEMBL256 |
4390.0 nM [Ki] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | ROLOFYLLINE Approved UseUnknown |
Doses
| Dose | Population | Adverse 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 |
PubMed
| Title | Date | PubMed |
|---|---|---|
| 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 |
|
| 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 |
|
| 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
Sample Use Guides
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
Edited
Fri Dec 15 15:56:48 UTC 2023
by
admin
on
Fri Dec 15 15:56:48 UTC 2023
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| Record UNII |
7805S5HIHX
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| Record Status |
Validated (UNII)
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| Record Version |
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C319
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DTXSID50929292
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C96195
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Rolofylline
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DB12670
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CHEMBL2103819
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7805S5HIHX
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11948288
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