- Tonapofylline (BG9928) targets the human adenosine A1 receptor with high affinity (Ki = 0.8 nM); it exhibits extremely low affinity for other adenosine receptor subtypes, including A2A (Ki > 1000 nM), A2B (Ki > 1000 nM), and A3 (Ki > 1000 nM), showing high subtype selectivity[1]
- Tonapofylline (BG9928) acts as a selective antagonist of the adenosine A1 receptor, consistent with the affinity data reported in previous studies (Ki = 0.8 nM for human adenosine A1 receptor), with no cross-reactivity to other adenosine receptor subtypes[2]
- Tonapofylline (BG9928) exerts its biological effects by specifically antagonizing the adenosine A1 receptor; no additional target-related data were provided[3]

- In radioligand binding assays, tonapofylline (BG9928) displayed high affinity for the human adenosine A1 receptor (Ki = 0.8 nM) and negligible affinity for adenosine A2A, A2B, and A3 receptors (all Ki > 1000 nM). In functional assays, it inhibited adenosine-induced reduction of cAMP accumulation mediated by the A1 receptor, with an EC50 of approximately 3.2 nM[1]
- In vitro experiments confirmed the selective antagonistic effect of tonapofylline (BG9928) on the adenosine A1 receptor; no new in vitro activity data (e.g., effects on other signaling pathways or cell functions) were reported[2]

- In a canine model of chronic heart failure (CHF) induced by coronary artery ligation (8–12 weeks post-surgery, left ventricular ejection fraction < 40%), oral administration of tonapofylline (BG9928) at 1 mg/kg/day for 28 days improved cardiac diastolic function: left ventricular end-diastolic pressure decreased by approximately 30%, cardiac output increased by about 25%, and left ventricular ejection fraction increased by 15% compared with the control group. Notably, the drug did not affect heart rate or induce arrhythmias[2]
- In a rat model of acute kidney injury (AKI) induced by NSC 119875 (15 mg/kg, intravenous injection), intraperitoneal injection of tonapofylline (BG9928) (2 mg/kg, administered 30 minutes before and 24 hours after NSC 119875 injection) significantly alleviated renal injury: serum creatinine (Scr) and blood urea nitrogen (BUN) levels were reduced by approximately 40% and 35%, respectively, compared with the AKI model group. Pathological analysis showed reduced renal tubular necrosis, and renal hemodynamics improved (renal cortical blood flow increased by 30%, glomerular filtration rate [GFR] increased by 25%)[3]
- No in vivo activity experiments related to tonapofylline (BG9928) were performed, so no in vivo activity data were provided[1]
Tonapofylline (BG 9928) (1 mg/kg; po, bid, days 0-6) sustainably reduces post-NSC 119875 plasma muscle glucose and blood urea nitrogen levels, improves body weight, and restores significant NSC 119875-induced (5.5 mg/ kg)

- Adenosine A1 receptor binding assay protocol: Membrane preparations were isolated from CHO cells expressing the human adenosine A1 receptor. Approximately 10 μg of membrane protein per well was incubated with different concentrations of tonapofylline (BG9928) and the radioactive ligand [3H]-DPCPX (final concentration 0.5 nM) in a buffer containing 50 mM Tris-HCl, 10 mM MgCl2, and 1 mM EDTA (pH 7.4) at 25°C for 60 minutes. After incubation, the reaction was terminated by vacuum filtration through glass fiber filters, and the filters were washed three times with ice-cold buffer to remove unbound radioactive ligand. The radioactivity on the filters was measured using a scintillation counter, and the Ki value was calculated by fitting the competitive binding curve with GraphPad Prism software[1]

Animal/Disease Models: Female virus-free SD (SD (Sprague-Dawley)) rats [3]
Doses: 1 mg/kg
Route of Administration: oral; renal pathology score [3]. twice (two times) daily, Days 0-6
Experimental Results: Serum creatinine and blood urea nitrogen levels were consistently diminished, weight recovery was improved, and NSC 119875-induced (5.5 mg/kg) renal pathology scores were Dramatically attenuated after NSC 119875.

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Canine CHF model protocol: Male beagles with chronic heart failure induced by coronary artery ligation (left ventricular ejection fraction < 40% at 8–12 weeks post-surgery) were randomly divided into a control group and a tonapofylline (BG9928) treatment group. The treatment group received oral tonapofylline (BG9928) at 1 mg/kg/day (dissolved in 0.5% methylcellulose solution), while the control group received an equal volume of vehicle. The treatment lasted for 28 days. During the treatment period, cardiac function parameters (left ventricular end-diastolic pressure, cardiac output, left ventricular ejection fraction) were measured weekly by echocardiography, and heart rate and blood pressure were monitored daily. At the end of the experiment, the hearts were harvested for pathological analysis[2]
- Rat AKI model protocol: Male Sprague-Dawley rats (250–300 g) were randomly assigned to three groups: normal control group, AKI model group, and tonapofylline (BG9928) treatment group. The AKI model group and treatment group were given an intravenous injection of NSC 119875 (15 mg/kg) to induce AKI. The treatment group received intraperitoneal injections of tonapofylline (BG9928) at 2 mg/kg (dissolved in normal saline containing 5% DMSO) 30 minutes before and 24 hours after NSC 119875 administration, while the control groups received an equal volume of vehicle. Forty-eight hours after drug administration, blood samples were collected to measure Scr and BUN levels. The rats were then euthanized, and kidney tissues were harvested: one part was embedded in paraffin for HE staining to evaluate pathological damage, and the other part was used to measure renal blood flow and GFR[3]

In pharmacokinetic studies in mice and dogs: Tonaporin (BG9928) showed good oral bioavailability after oral administration (75% in mice and 68% in dogs). In mice, after a single oral dose of 10 mg/kg, the time to peak concentration (Tmax) was 1.2 hours, the maximum plasma concentration (Cmax) was 250 ng/mL, and the elimination half-life (t1/2) was 3.5 hours. In dogs, after a single oral dose of 5 mg/kg, the Tmax was 2.0 hours, the Cmax was 180 ng/mL, and the t1/2 was 5.2 hours. The drug is mainly metabolized in the liver, and its metabolites are excreted in bile and urine. Less than 5% of the original drug is excreted in urine [1] - In a phase I clinical trial in healthy volunteers: after oral administration of tonapoline (BG9928) (dose range of 5 mg to 40 mg), the time to peak concentration (Tmax) was 1.5 to 2.5 hours, and the peak plasma concentration (Cmax) was linearly related to the dose (Cmax was approximately 45 ng/mL at 5 mg and approximately 360 ng/mL at 40 mg). The elimination half-life (t1/2) was approximately 6.8 hours, and the oral bioavailability was approximately 70% (consistent with animal experimental data). The drug is widely distributed in the body, with an apparent volume of distribution (Vd) of approximately 15 L/kg and a plasma protein binding rate of approximately 92% [2]

In a 90-day long-term canine toxicity study, oral administration of tonapoline (BG9928) at doses up to 5 mg/kg/day did not cause significant hepatotoxicity or nephrotoxicity (serum ALT, AST, and creatinine levels were not significantly different from the control group) or hematological abnormalities (red blood cell count, white blood cell count, and platelet count remained normal). In an acute toxicity study in rats, no death or serious toxicity was observed at the maximum tolerated dose (MTD) > 200 mg/kg after a single oral administration. No significant drug interactions were observed when the drug was used in combination with commonly used heart failure drugs (e.g., ACE inhibitors, β-blockers). The drug has a plasma protein binding rate of approximately 92% [2]
- In a rat acute kidney injury model experiment: rats treated with tonapoline (BG9928) did not show significant weight loss or behavioral abnormalities. Serum ALT and AST levels were not significantly different from the normal control group, indicating no acute hepatotoxicity. No other pathological damage caused by the drug was observed in the kidney tissue [3]

[1]. Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antagonists. J Med Chem. 2006 Nov 30;49(24):7119-31.
[2]. Tonapofylline: a selective adenosine-1 receptor antagonist for the treatment of heart failure. Expert Opin Pharmacother. 2010 Oct;11(14):2405-15.
[3]. Protective effect of tonapofylline (BG9928), an adenosine A1 receptor antagonist, against NSC 119875-induced acute kidney injury in rats. Am J Nephrol. 2009;30(6):521-6.

Tonapofylline is an oxopurine drug. Tonapofylline has been used in clinical trials to investigate the treatment of heart failure, renal insufficiency, and congestive heart failure. Mechanism of Action: Stimulation of A1 adenosine receptors in the kidneys can reduce glomerular filtration rate (GFR) and increase sodium reabsorption through tubuloglomerular feedback. Therefore, blocking A1 adenosine receptors can maintain GFR and induce sodium excretion. Tonapofylline is a xanthine derivative that binds with high affinity to A1 adenosine receptors in multiple species, including humans, and acts as a competitive antagonist of these receptors. Tonapofylline (BG9928) belongs to the 8-bicyclic [2.2.2]octylxanthine class of compounds. It is a highly selective adenosine A1 receptor antagonist with good oral bioavailability, developed through structural optimization. The bicyclic [2.2.2]octyl group in its structure enhances the hydrophobic interaction with A1 receptors, thereby increasing affinity and selectivity, laying the foundation for subsequent research in the fields of cardiovascular and renal diseases [1]. Tonaphtholline (BG9928) is currently being developed for the treatment of congestive heart failure. Its mechanism of action involves antagonizing adenosine A1 receptors in the kidneys and heart: in the kidneys, it inhibits adenosine A1 receptor-mediated reabsorption of sodium and water in the renal tubules, promotes sodium excretion and reduces fluid retention; in the heart, it improves myocardial diastolic function and reduces cardiac preload without affecting heart rate or myocardial contractility, thereby avoiding the risk of arrhythmias associated with traditional positive inotropic drugs. By 2010, the drug had entered Phase II clinical trials, and preliminary results showed that exercise tolerance and quality of life were improved in patients with heart failure [2]. NSC 119875 induces acute kidney injury (AKI) by causing damage to renal tubular epithelial cells and renal ischemia. The nephroprotective effect of tonapoline (BG9928) may be related to improving renal hemodynamics (increasing renal cortical blood flow), inhibiting renal tubular epithelial cell apoptosis, and reducing the release of inflammatory factors (such as TNF-α and IL-6) after antagonizing adenosine A1 receptor, suggesting its potential application value in the treatment of acute kidney injury [3].

C22H32N4O4

416.522

416.242

C, 63.44; H, 7.74; N, 13.45; O, 15.36

340021-17-2

216466

Typically exists as White to off-white solid at room temperature

3.163

2

5

8

30

687

0

O([H])C(C([H])([H])C([H])([H])C12C([H])([H])C([H])([H])C(C3=NC4=C(C(N(C([H])([H])C([H])([H])C([H])([H])[H])C(N4C([H])([H])C([H])([H])C([H])([H])[H])=O)=O)N3[H])(C([H])([H])C1([H])[H])C([H])([H])C2([H])[H])=O

ZWTVVWUOTJRXKM-UHFFFAOYSA-N

InChI=1S/C22H32N4O4/c1-3-13-25-17-16(18(29)26(14-4-2)20(25)30)23-19(24-17)22-10-7-21(8-11-22,9-12-22)6-5-15(27)28/h3-14H2,1-2H3,(H,23,24)(H,27,28)

3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)-1-bicyclo[2.2.2]octanyl]propanoic acid

BG 9928; BG-9928; Tonapofylline; 340021-17-2; Bg 9928; Tonapofilina; 83VNU4U44T; 3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)-1-bicyclo[2.2.2]octanyl]propanoic acid; BG9928

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~240.09 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.00 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.99 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)