MedKoo Cat#: 319899 | Name: Rolofylline
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Rolofylline, aslo known as KW-3902, is an experimental diuretic which acts as a selective adenosine A1 receptor antagonist. Development of rolofylline was terminated on September 1, 2009, after the results of a large clinical trial (PROTECT) showed the drug to be no better than placebo for patients with acute heart failure. Participants given rolofylline did show some improvement in shortness of breath, but the drug did not prevent kidney damage or have any significant effect on overall treatment success. Rolofylline was also associated with a higher incidence of seizures and stroke.

Chemical Structure

Rolofylline
Rolofylline
CAS#136199-02-5

Theoretical Analysis

MedKoo Cat#: 319899

Name: Rolofylline

CAS#: 136199-02-5

Chemical Formula: C20H28N4O2

Exact Mass: 356.2212

Molecular Weight: 356.47

Elemental Analysis: C, 67.39; H, 7.92; N, 15.72; O, 8.98

Price and Availability

Size Price Availability Quantity
5mg USD 190.00
10mg USD 350.00
25mg USD 750.00
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Related CAS #
No Data
Synonym
KW-3902; KW 3902; KW3902; Rolofylline
IUPAC/Chemical Name
8-((2R,3as,5S,6as)-hexahydro-2,5-methanopentalen-3a(1H)-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione
InChi Key
PJBFVWGQFLYWCB-OYEQCZOJSA-N
InChi Code
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-
SMILES Code
O=C(N1CCC)N(CCC)C2=C(NC([C@@]3([C@@H]4C5)C[C@H](C4)C[C@H]5C3)=N2)C1=O
Appearance
Solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Product Data
Biological target:
Rolofylline is metabolized primarily to the pharmacologically active M1-trans and M1-cis metabolites by cytochrome P450 (CYP450). Rolofylline alleviates presynaptic dysfunction and restores neuronal activity and dendritic spine levels in vitro. It is an interesting candidate to combat the hypometabolism and neuronal dysfunction associated with Tau-induced neurodegenerative diseases.
In vitro activity:
This article studied the effect of rolofylline on p-aminohippurate (PAH) transport in opossum kidney (OK) epithelial cells. Pretreatment with rolofylline inhibited the transcellular transport of PAH across OK cell monolayers. The pretreatment inhibited the uptake of PAH across the basolateral membrane of OK cells. Reference: Biochim Biophys Acta. 1999 Jul 15;1419(2):164-72. https://pubmed.ncbi.nlm.nih.gov/10407068/
In vivo activity:
Oral administration of rolofylline for 2-wk to 14-mo-old proaggregant Tau transgenic mice restores the spatial memory deficits and normalizes the basic synaptic transmission. Rolofylline is a potential candidate for combatting hypometabolism and neuronal dysfunction associated with Tau acculumation-induced neurodegenerative diseases. Reference: Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11597-11602. https://pubmed.ncbi.nlm.nih.gov/27671637/
Solvent mg/mL mM
Solubility
DMSO 20.0 56.11
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 356.47 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
1. Nagai J, Yano I, Habu Y, Katsura T, Hashimoto Y, Inui K. Inhibitory effect of KW-3902, an adenosine A(1) receptor antagonist, on p-aminohippurate transport in OK cells. Biochim Biophys Acta. 1999 Jul 15;1419(2):164-72. doi: 10.1016/s0005-2736(99)00061-9. PMID: 10407068. 2. Anglada-Huguet M, Endepols H, Sydow A, Hilgers R, Neumaier B, Drzezga A, Kaniyappan S, Mandelkow E, Mandelkow EM. Reversal of Tau-Dependent Cognitive Decay by Blocking Adenosine A1 Receptors: Comparison of Transgenic Mouse Models with Different Levels of Tauopathy. Int J Mol Sci. 2023 May 25;24(11):9260. doi: 10.3390/ijms24119260. PMID: 37298211; PMCID: PMC10252552. 3. Dennissen FJ, Anglada-Huguet M, Sydow A, Mandelkow E, Mandelkow EM. Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280. Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11597-11602. doi: 10.1073/pnas.1603119113. Epub 2016 Sep 26. PMID: 27671637; PMCID: PMC5068267.
In vitro protocol:
1. Nagai J, Yano I, Habu Y, Katsura T, Hashimoto Y, Inui K. Inhibitory effect of KW-3902, an adenosine A(1) receptor antagonist, on p-aminohippurate transport in OK cells. Biochim Biophys Acta. 1999 Jul 15;1419(2):164-72. doi: 10.1016/s0005-2736(99)00061-9. PMID: 10407068.
In vivo protocol:
1. Anglada-Huguet M, Endepols H, Sydow A, Hilgers R, Neumaier B, Drzezga A, Kaniyappan S, Mandelkow E, Mandelkow EM. Reversal of Tau-Dependent Cognitive Decay by Blocking Adenosine A1 Receptors: Comparison of Transgenic Mouse Models with Different Levels of Tauopathy. Int J Mol Sci. 2023 May 25;24(11):9260. doi: 10.3390/ijms24119260. PMID: 37298211; PMCID: PMC10252552. 2. Dennissen FJ, Anglada-Huguet M, Sydow A, Mandelkow E, Mandelkow EM. Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280. Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11597-11602. doi: 10.1073/pnas.1603119113
1: Cleland JG, Chiswell K, Teerlink JR, Stevens S, Fiuzat M, Givertz MM, Davison BA, Mansoor GA, Ponikowski P, Voors AA, Cotter G, Metra M, Massie BM, O'Connor CM. Predictors of postdischarge outcomes from information acquired shortly after admission for acute heart failure: a report from the 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 (PROTECT) Study. Circ Heart Fail. 2014 Jan;7(1):76-87. doi: 10.1161/CIRCHEARTFAILURE.113.000284. Epub 2013 Nov 26. PubMed PMID: 24281134. 2: He W, Wilder T, Cronstein BN. Rolofylline, an adenosine A1 receptor antagonist, inhibits osteoclast differentiation as an inverse agonist. Br J Pharmacol. 2013 Nov;170(6):1167-76. doi: 10.1111/bph.12342. PubMed PMID: 23962057; PubMed Central PMCID: PMC3838692. 3: Stroh M, Hutmacher MM, Pang J, Lutz R, Magara H, Stone J. Simultaneous pharmacokinetic model for rolofylline and both M1-trans and M1-cis metabolites. AAPS J. 2013 Apr;15(2):498-504. doi: 10.1208/s12248-012-9443-5. Epub 2013 Jan 25. PubMed PMID: 23355301; PubMed Central PMCID: PMC3675731. 4: Teerlink JR, Iragui VJ, Mohr JP, Carson PE, Hauptman PJ, Lovett DH, Miller AB, Piña IL, Thomson S, Varosy PD, Zile MR, Cleland JG, Givertz MM, Metra M, Ponikowski P, Voors AA, Davison BA, Cotter G, Wolko D, Delucca P, Salerno CM, Mansoor GA, Dittrich H, O'Connor CM, Massie BM. The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT. Drug Saf. 2012 Mar 1;35(3):233-44. doi: 10.2165/11594680-000000000-00000. PubMed PMID: 22339573. 5: Lim GB. Heart failure: rolofylline fails to improve renal function in patients with acute HF. Nat Rev Cardiol. 2011 May 31;8(7):363. doi: 10.1038/nrcardio.2011.82. PubMed PMID: 21629209. 6: Voors AA, Dittrich HC, Massie BM, DeLucca P, Mansoor GA, Metra M, Cotter G, Weatherley BD, Ponikowski P, Teerlink JR, Cleland JG, O'Connor CM, Givertz MM. Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). J Am Coll Cardiol. 2011 May 10;57(19):1899-907. doi: 10.1016/j.jacc.2010.11.057. PubMed PMID: 21545947. 7: Metra M, O'Connor CM, Davison BA, Cleland JG, Ponikowski P, Teerlink JR, Voors AA, Givertz MM, Mansoor GA, Bloomfield DM, Jia G, DeLucca P, Massie B, Dittrich H, Cotter G. Early dyspnoea relief in acute heart failure: prevalence, association with mortality, and effect of rolofylline in the PROTECT Study. Eur Heart J. 2011 Jun;32(12):1519-34. doi: 10.1093/eurheartj/ehr042. Epub 2011 Mar 8. PubMed PMID: 21388992. 8: Massie BM, O'Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, Weatherley BD, Cleland JG, Givertz MM, Voors A, DeLucca P, Mansoor GA, Salerno CM, Bloomfield DM, Dittrich HC; PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med. 2010 Oct 7;363(15):1419-28. doi: 10.1056/NEJMoa0912613. PubMed PMID: 20925544. 9: Ponikowski P, Mitrovic V, O'Connor CM, Dittrich H, Cotter G, Massie BM, Givertz MM, Chen E, Murray M, Weatherley BD, Fujita KP, Metra M. Haemodynamic effects of rolofylline in the treatment of patients with heart failure and impaired renal function. Eur J Heart Fail. 2010 Nov;12(11):1238-46. doi: 10.1093/eurjhf/hfq137. Epub 2010 Sep 7. PubMed PMID: 20823097. 10: Weatherley BD, Cotter G, Dittrich HC, DeLucca P, Mansoor GA, Bloomfield DM, Ponikowski P, O'Connor CM, Metra M, Massie BM; PROTECT Steering Committee, Investigators, and Coordinators. 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. J Card Fail. 2010 Jan;16(1):25-35. doi: 10.1016/j.cardfail.2009.10.025. Epub 2009 Dec 11. PubMed PMID: 20123315. 11: Stroh M, Dishy V, Radziszewski W, Hwang E, Lazarus-Shipitofsky N, Dittrich H, Johnson-Levonas AO, Lutz R, Wagner JA, Lai E. The effects of multiple doses of rolofylline on the single-dose pharmacokinetics of midazolam in healthy subjects. Am J Ther. 2010 Jan-Feb;17(1):53-60. doi: 10.1097/MJT.0b013e3181c12313. PubMed PMID: 20027108. 12: Radziszewski W, Lai E, Lazarus Shipitofsky N, Stroh M, Dishy V, Han L, Lewis W, Johnson-Levonas AO, Lutz R, Wagner J. A single supratherapeutic dose of rolofylline does not prolong the QTcF interval in healthy volunteers. Am J Ther. 2010 Jan-Feb;17(1):8-16. doi: 10.1097/MJT.0b013e3181c3cbdb. PubMed PMID: 20027105. 13: HOTLINE III: End of the line for rolofylline? Eur Heart J. 2009 Dec;30(23):2819-20. PubMed PMID: 19972641. 14: Slawsky MT, Givertz MM. Rolofylline: a selective adenosine 1 receptor antagonist for the treatment of heart failure. Expert Opin Pharmacother. 2009 Feb;10(2):311-22. doi: 10.1517/14656560802682213 . Review. PubMed PMID: 19236201. 15: Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O'Connor CM, Metra M, Massie BM; Protect Steering Committee, Investigators, and Coordinators. 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. J Card Fail. 2008 Oct;14(8):631-40. doi: 10.1016/j.cardfail.2008.08.010. Epub 2008 Sep 14. PubMed PMID: 18926433. 16: Chaparro S, Dittrich HC, Tang WW. Rolofylline (KW-3902): a new adenosine A1-receptor antagonist for acute congestive heart failure. Future Cardiol. 2008 Mar;4(2):117-23. doi: 10.2217/14796678.4.2.117. PubMed PMID: 19804290.