KW 3902

Rolofylline (KW-3902): a new adenosine A1-receptor antagonist for acute congestive heart failure.[Pubmed:19804290]

Future Cardiol. 2008 Mar;4(2):117-23.

Rolofylline (KW-3902 or MK-7418) is an adenosine A1-receptor antagonist that exerts its effect by blocking adenosine-mediated constriction of the afferent glomerular arteriole. By blocking A1 receptors, rolofylline increases the glomerular blood flow and filtration and inhibits sodium reabsorption in the proximal tubule, thereby enhancing natriuresis and diuresis. Early phase clinical research data provided the proof-of-concept of an incremental effect beyond standard diuretic therapy. A large Phase III program is currently ongoing for the intravenous formulation of rolofylline in the treatment of acute heart failure.

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.[Pubmed:17923351]

J Card Fail. 2007 Oct;13(8):609-17.

BACKGROUND: The kidney is the only organ in which adenosine is a paracrine vasoconstrictor. This raises the possibility of using adenosine A1 receptor (AA1R) antagonists to selectively vasodilate the kidney in conditions, such as congestive heart failure, in which a selective decrease in renal vascular resistance would be salutary. The present study was undertaken to test the effectiveness of an AA1R antagonist as a renal vasodilator in patients with reduced kidney function superimposed on congestive heart failure. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled, two-way crossover study was conducted in 32 outpatients with congestive heart failure and renal impairment (median glomerular filtration rate [GFR] 50 mL/min). Baseline GFR and renal plasma flow were assessed by iothalamate and para-amino-hippurate clearances, respectively, 3 hours before treatment. Subjects then received furosemide administered intravenously along with the AA1R antagonist, KW-3902 (rolofylline), or placebo. Clearance measurements were repeated, at intervals, throughout 8 hours beginning with the administration of the study drug. After a washout period of 3 to 8 days, subjects returned to undergo the crossover portion of the study. After the patients received KW-3902, GFR increased by 32% (P < .05 vs. placebo) and renal plasma flow increased by 48% (P < .005 vs. placebo) averaged over the ensuing 8 hours. Furthermore, those subjects who initially received KW-3902 returned for the crossover phase (median 6 days) with a persistent 10 mL/min increase in GFR more than their previous baseline (P < .05). CONCLUSIONS: AA1R activity contributes substantially to renal vascular tone in ambulatory patients with chronic congestive heart failure and impaired kidney function. Blockade of these receptors vasodilates the kidney and increases GFR. The increase in GFR seems to persist several days longer than predicted by pharmacokinetics, suggesting a resetting of one or more controllers among the complex network of physical and biological processes that interact to determine the kidney function. There may be short- or long-term benefits of using AA1R antagonists to improve kidney function in patients with congestive heart failure.

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.[Pubmed:17936154]

J Am Coll Cardiol. 2007 Oct 16;50(16):1551-60.

OBJECTIVES: This study sought to evaluate the dose-dependent effects of adenosine A1-receptor blockade on diuresis and renal function in patients with acute decompensated heart failure (ADHF) and renal impairment or diuretic resistance. BACKGROUND: Intravenous loop diuretics are the mainstay of therapy for patients with ADHF. Treatment, however, may be complicated by diuretic resistance and/or worsening renal function. METHODS: We carried out a pair of randomized, double-blind, placebo-controlled, proof-of-concept studies in 2 clinically challenging ADHF populations. RESULTS: In the ADHF protocol, 146 patients with volume overload and an estimated creatinine clearance (CrCl) of 20 to 80 ml/min were randomized to placebo or 1 of 4 doses of KW-3902 (rolofylline) infused over 2 h daily for up to 3 days. On day 1, KW-3902 monotherapy increased urine output during the first 6 h (445, 531, 631, and 570 ml in the 2.5-, 15-, 30-, and 60-mg groups, respectively) compared with placebo (374 ml; p = 0.02). On day 2, serum creatinine decreased in all KW-3902 groups and increased with placebo (p = 0.04). By day 4 or day of discharge if earlier, intravenous furosemide administration tended to be lower in the KW-3902 groups compared with placebo (p = 0.10). In the diuretic-resistant protocol, 35 patients with an average CrCl of 34 ml/min were randomized to a single infusion of placebo, 10, 30, or 60 mg of KW-3902. Compared with placebo, KW-3902 increased hourly urine volume and estimated CrCl with peak effects occurring at 2 to 3 h and at 24 h, respectively. Adverse events were not different between placebo and KW-3902. CONCLUSIONS: In patients with ADHF and volume overload, KW-3902, an adenosine A1-receptor antagonist, enhances the response to loop diuretics and may have a renal protective effect.

Clinical trials update from the European Society of Cardiology heart failure meeting: TNT subgroup analysis, darbepoetin alfa, FERRIC-HF and KW-3902.[Pubmed:16887387]

Eur J Heart Fail. 2006 Aug;8(5):547-9.

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the European Society of Cardiology heart failure meeting held in June 2006. All reports should be considered as preliminary data, as analyses may change in the final publication. In a sub-group analysis of the TNT study, intensive treatment with high-dose atorvastatin significantly reduced hospitalisations for heart failure in patients with stable coronary heart disease, compared with low-dose atorvastatin; this benefit was most evident in patients with a history of heart failure at baseline. In a combined analysis of two studies of darbepoetin alfa, which included 475 patients, treatment increased and maintained haemoglobin levels and produced non-significant improvements in symptoms and morbidity in anaemic heart failure patients compared to placebo. In the FERRIC-HF study (n=35), intravenous iron sucrose therapy improved exercise capacity and symptom status in iron-deficient heart failure patients. In a combined analysis of two studies (n=186), the adenosine A(1) receptor antagonist KW-3902 showed diuretic properties and appeared to enhance response to loop diuretics in heart failure patients hospitalised with fluid overload.

Adenosine A(1) receptor antagonist KW-3902 prevents hypoxia-induced renal vasoconstriction.[Pubmed:10565815]

J Pharmacol Exp Ther. 1999 Dec;291(3):988-93.

Studies were carried out to determine the intrarenal adenosine production during hypoxia, and the protective effects of a selective adenosine A(1) receptor antagonist 8-(noradamantan-3-yl)-1, 3-dipropylxanthine (KW-3902) on hypoxia-induced renal hemodynamic changes. We used an in vivo microdialysis method and measured the renal interstitial concentration of adenosine in response to hypoxic exposure in anesthetized mechanically ventilated rabbits. Normocapnic systemic hypoxia (PaO(2) = 32 +/- 6 mm Hg) caused a significant decrease in renal blood flow and increase in renal vascular resistance, indicating a renal vasoconstriction. The basal interstitial concentration of adenosine in the cortex was 293 +/- 70 nM, which was significantly higher than that in the medulla (170 +/- 23 nM). Five minutes after beginning hypoxia, the renal interstitial concentration of adenosine approximately tripled in the cortex and doubled in the medulla. During treatment with KW-3902, hypoxemia caused a similar increase in the adenosine concentration compared with that in the absence of KW-3902. The administration of KW-3902, however, significantly attenuated hypoxia-induced reduction in renal blood flow. These results suggest that adenosine was involved in hypoxia-induced renal vasoconstriction via its effects on adenosine A(1) receptors, and that KW-3902 had a partial protective effect against renal vasoconstriction during hypoxemia.

KW-3902, a selective high affinity antagonist for adenosine A1 receptors.[Pubmed:8732272]

Br J Pharmacol. 1996 Apr;117(8):1645-52.

1. We demonstrate that 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902) is a very potent and selective adenosine A1 receptor antagonist, assessed by radioligand binding and cyclic AMP response in cells. 2. In rat forebrain adenosine A1 receptors labelled with [3H]-cyclohexyladenosine (CHA), 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 (CGS21680), 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. 3. 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. A high positive correlation was observed between the pharmacological profile of adenosine ligands inhibiting the binding of [3H]-KW-3902 and that of [3H]-CHA. 4. KW-3902 showed potent A1 antagonism against the inhibition of forskolin-induced cyclic AMP accumulation in DDT1 MF-2 cells by the A1-selective agonist, cyclopentyladenosine with a dissociation constant (KB value) of 0.34 nM. KW-3902 antagonized 5'-N-ethylcarboxamidoadenosine-elicited cyclic AMP accumulation via A2B receptors with a KB value of 52 nM. 5. KW-3902 exhibited marked species-dependent differences in the binding affinities. The highest affinity was for the rat A1 receptor (ki = 0.19 nM) and these values for guinea-pig and dog A1 receptors were 1.3 and 10 nM, respectively.

8-Polycycloalkyl-1,3-dipropylxanthines as potent and selective antagonists for A1-adenosine receptors.[Pubmed:1548682]

J Med Chem. 1992 Mar 6;35(5):924-30.

With the aim of characterizing the hydrophobic interactions between xanthines and the A1 receptor site, 1,3-dipropyl-8-substituted xanthines were synthesized. Introduction of a quaternary carbon and the conformationally restricted cyclopentyl moiety into the 8-position of xanthines enhanced the adenosine A1 antagonism. 1,3-Dipropyl-8-(3-noradamantyl)xanthine was identified to be a selective and the most potent A1 receptor antagonist reported to date. Under our structure-activity relationship, the 8-substituent of xanthine antagonists and the N6-substituent of adenosine agonists appears to bind to the same region of the A1 receptor.

Rolofylline (KW-3902) is a potent, selective adenosine A1 receptor antagonist that is under development for the treatment of patients with acute congestive heart failure and renal impairment. Rolofylline is metabolized primarily to the pharmacologically active M1-trans and M1-cis metabolites by cytochrome P450 (CYP450). Rolofylline is alleviating the presynaptic dysfunction and restores neuronal activity as well as dendritic spine levels in vitro, is an interesting candidate to combat the hypometabolism and neuronal dysfunction associated with Tau-induced neurodegenerative diseases.

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