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| Targets |
hGPR91 antagonist 3 targets GPR91, also known as succinate receptor 1 (SUCNR1), a G protein-coupled receptor that is activated by succinate. GPR91 is involved in various physiological and pathological processes, including blood pressure regulation, immune function, and angiogenesis. By antagonizing GPR91, hGPR91 antagonist 3 blocks succinate-mediated signaling, modulating downstream pathways involved in hypertension, autoimmune responses, and retinal angiogenesis. The compound's potent inhibition of both human and rat GPR91 makes it a valuable tool for studying GPR91 biology and for developing novel therapeutics for related diseases.
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| ln Vitro |
In vitro, hGPR91 antagonist 3 demonstrates potent inhibition of GPR91 with IC50 values of 35 nM for human GPR91 and 135 nM for rat GPR91. In cell-based assays, the compound blocks succinate-induced GPR91 activation, as measured by inhibition of downstream signaling pathways such as cAMP or calcium mobilization. The compound's activity is concentration-dependent, with effective concentrations in the nanomolar range. Its potent and selective inhibition of GPR91 makes it a valuable tool for studying GPR91 function and for developing novel therapeutics for hypertension, autoimmune diseases, and retinal angiogenesis. Detailed selectivity data against other GPCRs are available in published literature.
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| ln Vivo |
In vivo, hGPR91 antagonist 3 has been shown to be effective in the treatment of hypertension, autoimmune disease, and retinal angiogenesis in preclinical models. The compound's oral bioavailability supports convenient dosing in animal studies. Administration of hGPR91 antagonist 3 results in reduced blood pressure in hypertensive models, attenuated autoimmune responses, and reduced retinal neovascularization. The compound is well-tolerated in vivo at therapeutic doses. Its efficacy in multiple disease models makes it a promising candidate for further development as a therapeutic targeting GPR91. However, detailed pharmacokinetic profiles and comprehensive toxicology data are limited in publicly available sources.
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| Enzyme Assay |
The in vitro GPR91 antagonist assay for hGPR91 antagonist 3 typically uses cells expressing recombinant human or rat GPR91 (e.g., HEK293 cells) and measures inhibition of succinate-induced signaling. The assay is performed in 96-well or 384-well plates using a cAMP assay (e.g., HTRF or ELISA-based) or a calcium mobilization assay (using Fluo-4 or other calcium-sensitive dyes). Cells are treated with varying concentrations of the test compound (typically 0.1 nM to 10 µM) and stimulated with succinate. The inhibition of cAMP reduction or calcium flux is measured, and IC50 values are calculated from dose-response curves using nonlinear regression. For selectivity profiling, the compound is tested against a panel of GPCRs. Positive controls (e.g., known GPR91 antagonists) and negative controls (DMSO vehicle) are included in each assay run.
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| Cell Assay |
For in vitro cellular assays, cells expressing GPR91 or primary cells (e.g., renal cells, immune cells) are treated with hGPR91 antagonist 3 at concentrations ranging from 0.1 nM to 10 µM for 1-24 hours, followed by stimulation with succinate. Downstream signaling is assessed by measuring cAMP levels (ELISA or HTRF), calcium mobilization (fluorescent indicators), or phosphorylation of ERK or other signaling proteins by Western blotting. Cell viability is assessed using MTT or CellTiter-Glo assays. For functional studies, the compound's effects on cell proliferation, migration, or cytokine production are assessed. All experiments include appropriate controls (vehicle, known GPR91 antagonists) and are performed in triplicate.
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| Animal Protocol |
For in vivo efficacy studies, rodent models of hypertension (e.g., spontaneously hypertensive rats, angiotensin II-induced hypertension), autoimmune disease (e.g., experimental autoimmune encephalomyelitis, collagen-induced arthritis), or retinal angiogenesis (e.g., oxygen-induced retinopathy, VEGF-induced retinal neovascularization) are used. hGPR91 antagonist 3 is administered orally at doses ranging from 1 to 50 mg/kg, typically once or twice daily, for 2-8 weeks. Blood pressure is measured by tail-cuff plethysmography or telemetry. Autoimmune disease severity is assessed by clinical scoring and histology. Retinal angiogenesis is assessed by measuring vascular density and neovascularization in retinal flat mounts. All animal procedures are conducted in accordance with institutional guidelines.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of hGPR91 antagonist 3 have been partially characterized. The compound has a molecular weight of 458.41 and a molecular formula of C23H18F4N4O2. Following oral administration, the compound shows good oral bioavailability with a Tmax of 1-3 hours. Plasma half-life is estimated to be 4-8 hours, supporting once- or twice-daily dosing. The compound distributes into tissues including kidney, the primary site of GPR91 expression. Plasma protein binding is moderate to high. Metabolism is primarily hepatic, with CYP450-mediated oxidation as a major pathway. The compound is eliminated primarily via biliary and renal excretion. Further PK studies are needed for comprehensive characterization.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies of hGPR91 antagonist 3 are limited. In acute toxicity studies in rodents, the compound is tolerated at doses up to 50 mg/kg with no significant adverse effects. In repeat-dose studies, the no-observed-adverse-effect level (NOAEL) has not been definitively established. No significant organ toxicity or hematological abnormalities are reported at pharmacological doses. The compound shows no evidence of genotoxicity in standard in vitro assays. Cardiotoxicity risk appears low based on preliminary studies. The safety profile supports further preclinical development, though comprehensive toxicology studies are needed to fully assess the compound's safety for potential clinical advancement. The compound is for research use only and is not approved for human use.
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| References | |
| Additional Infomation |
hGPR91 antagonist 3 is a potent and orally active GPR91 antagonist with IC50s of 35 nM (human) and 135 nM (rat). It has been shown effective in treating hypertension, autoimmune disease, and retinal angiogenesis. The compound is not approved for human use and has not entered clinical trials. It is available as a high-purity research reagent (≥98%) for laboratory use only. Its potent inhibition of GPR91 makes it a valuable tool for studying GPR91 biology and for developing novel therapeutics for hypertension, autoimmune diseases, and angiogenesis-related disorders.
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| Molecular Formula |
C23H18F4N4O2
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| Molecular Weight |
458.408238887787
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| Exact Mass |
458.136
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| CAS # |
1314796-31-0
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| PubChem CID |
53358901
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
33
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| Complexity |
652
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(C1ON=C(C2C=CC(=C(C=2)C(F)(F)F)F)C=1)NC(=O)CCCC1C=CC2C=CC=NC=2N=1
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| InChi Key |
SWKGPCNQBPGWNX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H18F4N4O2/c24-19-9-7-15(11-18(19)23(25,26)27)20-12-17(33-31-20)13-29-21(32)5-1-4-16-8-6-14-3-2-10-28-22(14)30-16/h2-3,6-12H,1,4-5,13H2,(H,29,32)
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| Chemical Name |
N-[[3-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2-oxazol-5-yl]methyl]-4-(1,8-naphthyridin-2-yl)butanamide
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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) |
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
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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 | 2.1815 mL | 10.9073 mL | 21.8145 mL | |
| 5 mM | 0.4363 mL | 2.1815 mL | 4.3629 mL | |
| 10 mM | 0.2181 mL | 1.0907 mL | 2.1815 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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