Phosphodiesterase (PDE) peak III (IC50 = 0.7 μM in canine left ventricle)
No effect on ventricular PDE peak I (IC50 > 100 μM)
In 180- to 200-day-old myopathic hamster, PDE peak III inhibition was weak (IC50 = 300 μM). [2]

Orally administered prinoxodan (RG W-2938) is an inotrope/vasodilator. In vitro testing on isolated guinea pig hearts revealed that Prinoxodan, a new non-glycoside, non-catecholamine cardiotonic/vasodilator, increased contractility in a dose-related manner [2].

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In isolated guinea pig hearts (Langendorff preparation), Prinoxodan at concentrations from 5 nmol to 5 μmol increased developed pressure (dP) and dP/dt in a concentration‑related manner. The maximum increases were 51 ± 16% for dP and 68 ± 5% for dP/dt after 5 μmol. Heart rate was slightly increased (max +6 ± 2% at 5 μmol). Coronary vascular resistance was not significantly altered. Vehicle treatment did not affect dP, dP/dt, or coronary resistance but caused a slight decrease in HR (−8 ± 4%). [2]

In vivo tests on anesthetized and awake dogs were conducted on Prinoxodan (RG W-2938), a new nonglycoside, noncatecholamine cardiotonic/vasodilator. When administered intravenously (30–300 μg/kg), prinoxodan 30-300 μg/kg reduces total peripheral resistance (TPR) and arterial pressure in a dose-related manner in dogs under anesthesia. It also enhances contractility. Aortic blood flow did not vary considerably, and heart rate (HR) only marginally rose. When a single oral dose of Prinoxodan 0.3 mg/kg was given to conscious chronically instrumented dogs, the result was only a slight rise in heart rate (15–240 minutes after treatment), but the increase in contractility was substantial and long-lasting. A mecamylamine-propranolol-induced heart failure model was used to study the effects of intravenous propranolol 30-300 μg/kg. By boosting myocardial contractility and lowering arterial pressure, prinoxodan successfully cures drug-induced heart failure while having a minimally negative impact on HR[2].

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In anesthetized dogs, i.v. Prinoxodan (30‑300 μg/kg) dose‑dependently increased contractile force (max +94 ± 12% at 100 μg/kg), slightly increased HR (max +26 ± 5%), decreased mean arterial pressure (MAP, max −39 ± 4% at 300 μg/kg) and total peripheral resistance (TPR, max −37 ± 6%), with no significant change in aortic flow. [2]
In mecamylamine‑propranolol‑induced myocardial depression in anesthetized dogs, Prinoxodan (30‑300 μg/kg i.v.) effectively reversed heart failure: contractile force increased (e.g., +125 ± 18% at 100 μg/kg, +166 ± 25% at 300 μg/kg), MAP decreased (−25 ± 4% at 100 μg/kg, −38 ± 5% at 300 μg/kg), TPR decreased (−42 ± 4% at 100 μg/kg, −54 ± 2% at 300 μg/kg), HR slightly increased (+19 ± 4% at 300 μg/kg), and aortic flow was unchanged. ED50 for inotropy was 32 μg/kg i.v. At ED50, HR increased 10%, MAP decreased 12%, TPR decreased 31%. [2]
In conscious chronically instrumented dogs, oral Prinoxodan (0.1, 0.3, 1 mg/kg p.o.) dose‑dependently increased LV dP/dt (e.g., +44 ± 10% at 0.3 mg/kg, +61 ± 12% at 1 mg/kg) with minimal HR changes (max +21 ± 4 beats/min at 1 mg/kg). MAP, LVEDP, and rate‑pressure product were not significantly changed. Onset 15‑30 min, peak at 1 h. A single oral dose of 0.3 mg/kg produced sustained increase in dP/dt for >4 h (peak 50‑60% increase between 75‑240 min) with only slight HR increase (15 beats/min). [2]

Phosphodiesterase (PDE) peak III inhibition was measured in canine left ventricle. Prinoxodan inhibited PDE peak III with an IC50 of 0.7 μM, while it had no effect on ventricular PDE peak I (IC50 > 100 μM). In the 180- to 200-day-old myopathic hamster, the compound was a much weaker inhibitor of PDE peak III with an IC50 of 300 μM, whereas milrinone had an IC50 of 14 μM in the same preparation. [2]

Anesthetized dog studies: Adult mongrel dogs (10‑15 kg) anesthetized with pentobarbital sodium (35 mg/kg i.v.), ventilated with room air. Instrumentation included femoral artery cannulation for blood pressure, femoral vein for drug infusion, left lateral thoracotomy, Walton‑Brodie strain gauge sutured to left ventricle for contractile force, and electromagnetic flow probe around aortic root for aortic flow. After stabilization, isoproterenol (0.3 μg/kg i.v.) was given to verify preparation integrity. Prinoxodan (30, 100, 300 μg/kg) was infused i.v. in ascending doses at 30‑min intervals (1.5 ml/min, total volume 3.5 ml). Effects were monitored continuously. [2]
Mecamylamine‑propranolol‑induced myocardial depression model: Anesthetized dogs prepared as above plus jugular vein cannulation and carotid artery isolation. After baseline, bilateral carotid occlusion (30 s) and isoproterenol challenge confirmed integrity. Myocardial depression was induced by mecamylamine (2 mg/kg i.v.) followed by propranolol (1 mg/kg i.v. + 0.3 mg/kg/h). After 20 min, BCO and ISO challenges repeated to confirm ganglionic and β‑blockade. Test compounds (same doses) infused i.v. in ascending doses at 30‑min intervals. [2]
Conscious dog studies: Beagle dogs (12‑17 kg) chronically instrumented with Konigsberg pressure transducer in left ventricle and aortic cannula. After ≥14 days recovery, dogs trained to lie quietly for 6 h. Fasted 18 h before study. Prinoxodan suspended in 0.5% methylcellulose and administered by gavage in constant 8 ml volume. For ascending dose studies, doses 0.1, 0.3, 1 mg/kg p.o. at 60‑min intervals. For single dose duration study, 0.3 mg/kg p.o. monitored for 4 h. Vehicle control was 0.5% methylcellulose. [2]
For i.v. studies, Prinoxodan was solubilized in polyethylene glycol (PEG)‑200 and serially diluted with PEG‑200. All solutions prepared fresh daily. [2]

[1]. [Evaluation of a new cardiotonic agent on human isolated atrium]. Ann Cardiol Angeiol (Paris). 1993 Feb;42(2):79-82.

[2]. Pharmacology of RG W-2938: a cardiotonic agent with vasodilator activity. J Cardiovasc Pharmacol. 1990 Oct;16(4):537-45.

Prinoxodan is an orally effective positive inotropic/vasodilator agent. Its mechanism involves PDE peak III inhibition, but additional mechanisms are suspected because in myopathic hamsters it increased contractility (38%) similarly to milrinone (39%) despite being much weaker as a PDE inhibitor (IC50 300 μM vs. 14 μM). The compound reduces afterload (decreased TPR) without significantly increasing myocardial oxygen demand. It was reported to be in phase II clinical trials for heart failure at the time of publication. [2]

C13H14N4O2

258.27600

258.111

111786-07-3

5362397

White to yellow solid powder

1.47g/cm3

1.724

1.118

2

3

1

19

434

0

SUCNEHPNQBBVHQ-UHFFFAOYSA-N

InChI=1S/C13H14N4O2/c1-17-7-9-6-8(2-3-10(9)14-13(17)19)11-4-5-12(18)16-15-11/h2-3,6H,4-5,7H2,1H3,(H,14,19)(H,16,18)

3-methyl-6-(6-oxo-4,5-dihydro-1H-pyridazin-3-yl)-1,4-dihydroquinazolin-2-one

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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