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Purity: ≥98%
PKG drug G1 is a novel electrophilic agent that activates PKG Iα by selectively targeting C42 of PKG Iα. Through a mechanism independent of C42 PKG Iα, PKG drug G1 can couple to vasodilation and lower blood pressure. One of the biggest health burdens today is arterial hypertension. Therapeutic potential exists in the development of novel antihypertensive medications that activate vasodilatory mechanisms not previously utilized by treatments. Oxidants cause an interprotein disulfide at position C42 in PKG Iα (protein kinase G Iα), which is linked to its activation and targeting, lowering blood pressure and causing vasodilation. PKG medication G1 may be a novel antihypertensive with a different mode of action than existing treatments. This led to the discovery of a medication that we will refer to as G1, which inhibits PKG Iα's C42 to cause isolated resistance blood vessels to dilate and lower blood pressure in a mouse model of angiotensin II-induced hypertension. However, in C42S PKG Iα knockin mice that were hypertensive due to angiotensin II, these antihypertensive effects were absent. Because the reactive cysteinyl thiol in these transgenic mice was altered to a hydroxyl, it was rendered incapable of reacting with electrophiles like medication G1 or endogenous vasodilatory oxidants. Consequently, these investigations validate PKG Iα C42 as the G1 target and demonstrate the feasibility of a novel class of antihypertensive medications that may be developed further for human clinical use.
| Targets |
PKG Iα
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| ln Vivo |
PKG drug G1 induces vasodilation of isolated resistance blood vessels and blood pressure lowering in a mouse model of angiotensin II–induced hypertension. The effectiveness of PKG medication G1 in relaxing WT arteries is evaluated in a murine model of hypertension, whereas KI vessels do not relax as well. In vivo, PKG medication G1 reduces blood pressure in hypertensive WT mice but not in KI mice. PKG medication G1 is tested in vivo in robust mice fitted with telemetric implants that enable continuous monitoring of heart rate and blood pressure. Intraperitoneal injection of PKG drug G1 or vehicle control is administered, and the acute effect on hemodynamics is evaluated. When PKG drug G1 is given at a dose of 7.4 mg/kg, blood pressure does not drop; however, reflex tachycardia occurs concurrently. When this is repeated with a dose of PKG medication G1 of 14.8 mg/kg, blood pressure is not changed; however, the higher dose causes a potentiated increase in heart rate[1].
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| Animal Protocol |
Mice: Mice on a pure C57BL/6 background are generated to constitutively express PKG Iα Cys42Ser. All experiments use male mice, either WT or PKG Iα Cys42Ser KI, that are age and body weight matched. In conscious, free-moving mice, radio telemetry is used to measure blood pressure and heart rate. Angiotensin II is administered via Alzet osmotic mini-pumps at a daily dose of 1.1 mg/kg in certain studies. PKG medication G1 is administered orally (20 mg/kg) in certain studies, or intraperitoneally (3.7–14.8 mg/kg). In order to provide PKG drug G1 orally, it is suspended in water and set in gelatin that has been flavored with sodium saccharin, so there is no stress or chance of the telemetric probe catheter coming loose[1].
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| References |
| Molecular Formula |
C13H11N3OS
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| Molecular Weight |
257.31
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| Exact Mass |
257.06
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| Elemental Analysis |
C, 60.68; H, 4.31; N, 16.33; O, 6.22; S, 12.46
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| CAS # |
374703-78-3
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| Related CAS # |
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| PubChem CID |
135402990
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| Appearance |
Light brown to reddish brown solid powder
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| LogP |
1.2
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
18
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| Complexity |
493
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC\1=NC2=CC=CC=C2/C1=C/C3=C(NC(=S)N3)O
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| InChi Key |
BPJCCABLAZZIEJ-RMKNXTFCSA-N
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| InChi Code |
InChI=1S/C13H11N3OS/c1-7-9(6-11-12(17)16-13(18)15-11)8-4-2-3-5-10(8)14-7/h2-6,17H,1H3,(H2,15,16,18)/b9-6+
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| Chemical Name |
4-hydroxy-5-[(Z)-(2-methylindol-3-ylidene)methyl]-1,3-dihydroimidazole-2-thione
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.8864 mL | 19.4318 mL | 38.8636 mL | |
| 5 mM | 0.7773 mL | 3.8864 mL | 7.7727 mL | |
| 10 mM | 0.3886 mL | 1.9432 mL | 3.8864 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.
Overview of dibromobimane screening method and its validation.
Drug G1-induced vasodilation involves cGMP-independent activation of PKG Iα (protein kinase G Iα).Hypertension. 2017 Sep; 70(3): 577–586. |
Screening candidate compounds for their ability to dilate mesenteric vessels by specifically targeting PKG Iα (protein kinase G Iα) C42.Hypertension. 2017 Sep; 70(3): 577–586. |
Drug G1 lowers blood pressure in hypertensive but not normotensive wild-type (WT) mice.
Oral drug G1 functions as an effective antihypertensive by targeting C42 of PKG Iα (protein kinase G Iα). |
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