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Purity: ≥98%
DJ-V-159 is a novel and potent agonist for G protein-coupled receptor family C group 6 member A (GPRC6A) with the potential for treating type 2 diabetes mellitus (T2D). GPRC6A is a potential therapeutic target for the treatment of type 2 diabetes mellitus (T2D), according to new insights into the regulation of glucose metabolism by β-cells, skeletal muscle, and liver hepatocytes via G protein coupled receptors. A small molecule medication that activates GPRC6A offers a potentially game-changing chance to simultaneously address several metabolic abnormalities that underpin type 2 diabetes (T2D), such as aberrant β-cell proliferation, insulin secretion, and peripheral insulin resistance. DJ-V-159 was found to stimulate GPRC6A signaling in a heterologous cell expression system in a dose-dependent manner through experimental testing. DJ-V-159 exhibited the highest efficacy in inducing β-cell insulin secretion and reducing serum glucose levels in mice of the wild-type.
| Targets |
GPRC6A
DJ-V-159 activates ERK in HEK-293 transfected with GPRC6A but not in non-transfected HEK-293 cells, with potency similar to L-Arg. Furthermore, DJ-V-159 induces GPRC6A-expressing HEK-293 cells to produce cAMP in a dose-dependent manner; this response is seen at 0.2 nM concentrations in the media. DJ-V-159 induces mouse beta-cell MIN-6 cells to secrete insulin. In MIN-6 cells, DJ-V-159 raised the insulin stimulation index (SI) in a manner akin to that of Ocn, a known GPRC6A ligand[1]. |
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| ln Vitro |
DJ-V-159 activates ERK in HEK-293 transfected with GPRC6A but not in non-transfected HEK-293 cells, with potency similar to L-Arg. Furthermore, DJ-V-159 induces GPRC6A-expressing HEK-293 cells to produce cAMP in a dose-dependent manner; this response is seen at 0.2 nM concentrations in the media. DJ-V-159 induces mouse beta-cell MIN-6 cells to secrete insulin. In MIN-6 cells, DJ-V-159 raised the insulin stimulation index (SI) in a manner akin to that of Ocn, a known GPRC6A ligand[1].
DJ-V-159 dose-dependently stimulated ERK phosphorylation in HEK-293 cells transfected with mouse GPRC6A, but not in non-transfected HEK-293 cells, with potency similar to L-arginine [1] DJ-V-159 dose-dependently stimulated cAMP production in GPRC6A-expressing HEK-293 cells, achieving a significant response at a media concentration of 0.2 mM [1] DJ-V-159 (0, 10⁻⁹, 10⁻⁸, 10⁻⁷, 10⁻⁶, 10⁻⁵, and 10⁻⁴ M) showed no cytotoxicity in HEK-293 cells after 72 hours of treatment, as determined by relative viable cell number [1] DJ-V-159 did not stimulate ERK phosphorylation in HEK-293 cells transfected with the closely-related calcium sensing receptor (CaSR), indicating selectivity [1] DJ-V-159 did not activate androgen receptor (AR) signaling in HEK-293 cells, indicating specificity for GPRC6A over AR [1] DJ-V-159 stimulated insulin secretion in mouse pancreatic β-cell line MIN-6 cells, increasing the insulin stimulation index similarly to the known GPRC6A ligand osteocalcin [1] |
| ln Vivo |
DJ-V-159 at 60 and 90 minutes following intraperitoneal injection of 10 mg/kg, lowers blood glucose levels in wildtype mice; in contrast, the vehicle (95% PEG + 5% DMSO) has no effect on blood glucose. At 60 and 90 minutes following intraperitoneal injection of 10 mg/kg, DJ-V-159 lowers blood glucose levels in wild-type mice by 43.6% and 41.9%, respectively. The mice showed no obvious side effects from this brief exposure to DJ-V-159. However, DJ-V-159 is either inside or close to the edge of Lipinski's Rule of Five[1].
Intraperitoneal administration of DJ-V-159 at 10 mg/kg significantly reduced blood glucose levels in wild-type C57BL/6 mice at 60 and 90 minutes post-injection, by 43.6% and 41.9% respectively, compared to vehicle-treated controls [1] The glucose-lowering effect of DJ-V-159 (10 mg/kg) was comparable in magnitude to that of metformin (300 mg/kg) administered intraperitoneally [1] Mice tolerated short-term exposure to DJ-V-159 without any overt side-effects [1] |
| Cell Assay |
ERK phosphorylation assay: HEK-293 cells transfected with or without mouse GPRC6A cDNA were made quiescent by overnight serum starvation and then stimulated with DJ-V-159 or other ligands. ERK activation was assessed 5–30 minutes after treatment by Western blot analysis using phospho-ERK1/2 and total ERK1/2 antibodies [1]
cAMP accumulation assay: GPRC6A-expressing HEK-293 cells were treated with DJ-V-159, and cAMP production was measured [1] Cytotoxicity assay: HEK-293 cells were treated with DJ-V-159 at various concentrations (0 to 10⁻⁴ M) for 72 hours, after which relative viable cell number was determined [1] Selectivity assay: HEK-293 cells transfected with human calcium sensing receptor (CaSR) or human androgen receptor (AR) were treated with DJ-V-159, and receptor activation was assessed via ERK phosphorylation (for CaSR) or AR-specific reporter assay [1] Insulin secretion assay: Mouse pancreatic β-cell line MIN-6 cells were pre-incubated in low glucose medium, then treated with DJ-V-159 or osteocalcin in a HEPES-balanced salt solution. Insulin concentration in the stimulation media was measured, and the stimulation index was calculated as the ratio of insulin in treatment versus control media [1] |
| Animal Protocol |
Mice: Eight to ten weeks prior, wild type C57BL/6 mice were given an intraperitoneal injection of either ${DJ-V-159} (10 mg/kg body weight), 300 mg/kg body weight of metformin, or a vehicle (95% PEG + 5% DMSO; 10 μL/g body weight). The mice were then fasted for five hours. After injection, blood glucose levels are checked 0, 30, 60, and 90 minutes later[1].
Wild-type C57BL/6 mice (8 to 10 weeks old) were fasted for 5 hours, then injected intraperitoneally with DJ-V-159 (10 mg/kg body weight) dissolved in vehicle (95% PEG + 5% DMSO) at a volume of 10 μl/g body weight [1] Blood glucose levels were measured at 0, 30, 60, and 90 minutes after injection using blood glucose strips and a glucometer [1] |
| References | |
| Additional Infomation |
DJ-V-159 (N¹,N³-bis(4-cyano-3-(trifluoromethyl)phenyl)isophthalamide) is a novel triphenyl compound. The lead compound A03 obtained by computer screening was prepared by chemical modification of aniline and isophthaloyl chloride [1]. DJ-V-159 is a GPRC6A small molecule agonist. It was obtained by screening using a structure-based virtual high-throughput screening method using a homology model of the Venus flytrap (VFT) domain and the 7-transmembrane (7-TM) domain of the acceptor [1]. DJ-V-159 has a molecular weight of 502.37 and barely conforms to Lipinski's five rules (calculated Log P = 5.55, hydrogen bond donor/acceptor = 4 or 6, number of atoms = 48). [1]
DJ-V-159 is a potential lead compound that can treat type 2 diabetes by activating GPRC6A, which regulates insulin secretion, glucose metabolism, and inter-organ hormone communication. [1] |
| Molecular Formula |
C24H12F6N4O2
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| Molecular Weight |
502.37
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| Exact Mass |
502.09
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| Elemental Analysis |
C, 57.38; H, 2.41; F, 22.69; N, 11.15; O, 6.37
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| CAS # |
2253744-53-3
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| Related CAS # |
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| PubChem CID |
137319717
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| Appearance |
White to off-white solid powder
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| LogP |
4.8
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
36
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| Complexity |
845
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
VEVNLJLJLVESLL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H12F6N4O2/c25-23(26,27)19-9-17(6-4-15(19)11-31)33-21(35)13-2-1-3-14(8-13)22(36)34-18-7-5-16(12-32)20(10-18)24(28,29)30/h1-10H,(H,33,35)(H,34,36)
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| Chemical Name |
1-N,3-N-bis[4-cyano-3-(trifluoromethyl)phenyl]benzene-1,3-dicarboxamide
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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 | 1.9906 mL | 9.9528 mL | 19.9056 mL | |
| 5 mM | 0.3981 mL | 1.9906 mL | 3.9811 mL | |
| 10 mM | 0.1991 mL | 0.9953 mL | 1.9906 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.
Docking of amino acids to GPRC6A VFT homology model.
The molecular structures of the compounds with high binding score for GPRC6A from computational screening.. From: Computationally identified novel agonists for GPRC6A.PLoS One.2018 Apr 23;13(4):e0195980. |
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The results for novel tri-phenyl compounds.
In vivo effects of DJ-V-159.. From: Computationally identified novel agonists for GPRC6A.PLoS One.2018 Apr 23;13(4):e0195980. |
Function analysis of novel compound, DJ-V-159 in vitro.. From: Computationally identified novel agonists for GPRC6A.
The molecular structures from GPRC6A homology modeling. |
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