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| Targets |
Soluble guanylate cyclase (sGC), a key enzyme in the NO signaling pathway. Praliciguat is a potent and orally active stimulator of sGC with an EC50 of 197 nM in HEK-293 cells. By stimulating sGC, the compound enhances the production of cyclic GMP (cGMP), leading to vasodilation, anti-inflammatory, and antifibrotic effects. The compound works through a NO-independent mechanism to stimulate sGC.
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| ln Vitro |
Praliciguat stimulates sGC in HEK-293 cells with an EC50 of 197 nM. The compound enhances NO signaling and acts as a vasodilator. It elicits hemodynamic, anti-inflammatory, and antifibrotic effects in preclinical models of metabolic dysfunction. The compound produces dose-related increases in plasma cGMP consistent with stimulation of sGC and shows sustained decreases in blood pressure with repeated once-daily dosing.
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| ln Vivo |
Praliciguat has been evaluated in multiple clinical trials. In a Phase 2 study (CAPACITY HFpEF), the compound was evaluated for safety and efficacy over 12 weeks in patients with heart failure with preserved ejection fraction. In an exploratory trial in participants with type 2 diabetes and hypertension, Praliciguat (40 mg once daily or 20 mg twice daily) was well tolerated over 14 days and showed positive trends in metabolic and blood pressure variables. The compound has also been studied in FSGS patients.
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| Enzyme Assay |
The in vitro enzyme assay for Praliciguat typically involves measuring the activity of recombinant soluble guanylate cyclase in a cell-free system. The enzyme is incubated with the substrate GTP and the test compound at various concentrations. The production of cGMP is quantified using immunoassays or radiometric methods, and the EC50 value is determined from the dose-response curve. The compound's ability to enhance NO signaling can also be assessed.
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| Cell Assay |
The in vitro cellular assay for Praliciguat typically involves the use of HEK-293 cells expressing sGC. Cells are treated with varying concentrations of the compound, and the intracellular cGMP levels are measured using ELISA or other immunoassays. The EC50 value is determined from the dose-response curve. The compound's effects on NO signaling and vasodilation can also be assessed using appropriate cellular models.
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| Animal Protocol |
In vivo animal studies for Praliciguat typically involve the use of rodent models of metabolic dysfunction, hypertension, or heart failure. Animals are administered the compound via oral gavage at various doses. Hemodynamic parameters such as blood pressure are measured, and markers of inflammation and fibrosis are assessed in tissues. The compound's effects on cGMP levels and vasodilation are evaluated to confirm target engagement.
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| ADME/Pharmacokinetics |
Praliciguat is orally active with favorable pharmacokinetic properties. It has a molecular weight of 534.36 g/mol and a molecular formula of C21H14F8N6O2. The compound shows good solubility in DMSO (250 mg/mL) and has been formulated for oral administration in clinical trials. It produces dose-related increases in plasma cGMP and shows sustained effects with repeated dosing.
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| Toxicity/Toxicokinetics |
Praliciguat has been evaluated in multiple clinical trials and has shown a favorable safety profile. In an exploratory trial in participants with type 2 diabetes and hypertension, the compound was well tolerated over 14 days, except for a single serious adverse event (SAE). In healthy subjects, multiple-ascending-dose studies showed that all doses were tolerated. The compound is intended for research use and further clinical development.
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| References | |
| Additional Infomation |
Praliciguat, a pyrazole compound, has the chemical name 5-fluoro-2-(1H-pyrazol-3-yl)pyrimidine, with a 2-fluorobenzyl group at position 1, a 1,2-oxazol-3-yl group at position 5, and a [3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl]nitrile group at position 4. It is a soluble guanylate cyclase activator currently in clinical development for the treatment of heart failure with preserved ejection fraction. It possesses various pharmacological effects, including soluble guanylate cyclase activation, anti-inflammatory, vasodilatory, and antihypertensive effects. It belongs to the isoxazole, pyrazole, organofluorine, aminopyrimidine, tertiary alcohol, secondary amino, and monofluorobenzene classes.
Praliciguat is currently being investigated in the clinical trial NCT03254485 (a study of the effects of IW-1973 on exercise capacity in patients with heart failure with preserved ejection fraction (HFPEF)). Praliciguat is also known as IW-1973 and is a soluble guanylate cyclase stimulator. It has been investigated in clinical trials for the treatment of heart failure with preserved ejection fraction (CAPACITY HFpEF), type 2 diabetes and hypertension, and focal segmental glomerulosclerosis (FSGS). The compound enhances NO signaling and acts as a vasodilator. It has shown promising results in preclinical studies. The molecular formula is C21H14F8N6O2. |
| Molecular Formula |
C21H14F8N6O2
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|---|---|
| Molecular Weight |
534.36209154129
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| Exact Mass |
534.105
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| CAS # |
1628730-49-3
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| PubChem CID |
86269973
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| Appearance |
White to off-white solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
15
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
37
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| Complexity |
748
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C(C(F)(F)F)(CNC1C(=CN=C(C2C=C(C3C=CON=3)N(CC3C=CC=CC=3F)N=2)N=1)F)O)(F)F
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| InChi Key |
CYSJNTQNMDWAJV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H14F8N6O2/c22-12-4-2-1-3-11(12)9-35-16(14-5-6-37-34-14)7-15(33-35)18-30-8-13(23)17(32-18)31-10-19(36,20(24,25)26)21(27,28)29/h1-8,36H,9-10H2,(H,30,31,32)
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| Chemical Name |
1,1,1,3,3,3-hexafluoro-2-[[[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(1,2-oxazol-3-yl)pyrazol-3-yl]pyrimidin-4-yl]amino]methyl]propan-2-ol
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| Synonyms |
IW1973, IW-1973 Praliciguat
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~250 mg/mL (~467.85 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.89 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.89 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8714 mL | 9.3570 mL | 18.7140 mL | |
| 5 mM | 0.3743 mL | 1.8714 mL | 3.7428 mL | |
| 10 mM | 0.1871 mL | 0.9357 mL | 1.8714 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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