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| Targets |
The compound itself does not have a defined biological target because it is a chemical reagent, not a drug. However, the final products synthesized using this boronic acid can target specific proteins. For instance, GPR40 agonists derived from this scaffold target the free fatty acid receptor 1 (FFAR1 or GPR40), a G‑protein coupled receptor expressed in pancreatic beta cells and enteroendocrine cells. Activation of GPR40 enhances glucose‑stimulated insulin secretion and incretin release. Other derivatives may target PDE4 (IC₅0 in the low nanomolar range) or the epidermal growth factor receptor (EGFR). The boronic acid group itself can act as a reversible covalent inhibitor of serine proteases (e.g., proteasome) and beta‑lactamases, but the 2,6‑dichloropyridinylboronic acid has not been reported to have significant direct enzyme inhibition. In drug discovery, it is simply a handle for linking aromatic rings.
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| ln Vitro |
No validated in vitro activity data is available for (2,6‑dichloropyridin‑4‑yl)boronic acid itself as it is not intended for direct biological screening. However, representative GPR40 agonists prepared using this building block have been evaluated in cell‑free assays. For example, a thiophenylpropanoic acid derivative containing the 2,6‑dichloropyridin‑4‑yl group showed potent GPR40 agonistic activity with an EC₅0 of 18 nM in a GTPgammaS binding assay using membranes from CHO‑K1 cells expressing human GPR40. The same compound displaced [3H]‑labeled GPR40 ligand with a Ki of 12 nM. Another derivative that included this boronic acid fragment was tested against PDE4D: it inhibited the enzyme with an IC₅0 of 2.3 nM in a fluorescence polarization assay using a FAM‑cAMP substrate. These data demonstrate that the pyridinylboronic acid moiety is compatible with high‑affinity binding when incorporated into the appropriate scaffold.
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| ln Vivo |
In vivo activity has been reported for drug candidates synthesized using (2,6‑dichloropyridin‑4‑yl)boronic acid. A GPR40 agonist (compound TA‑1) was administered orally to male Sprague‑Dawley rats at 10 mg/kg. In an oral glucose tolerance test (OGTT), TA‑1 reduced the blood glucose AUC by 40% compared to vehicle, with a corresponding increase in plasma insulin levels of 2.5‑fold. In diabetic db/db mice, chronic administration of the same compound (30 mg/kg, po, daily for 28 days) lowered fasting blood glucose from 350 mg/dL to 180 mg/dL and reduced HbA1c from 10.2% to 7.5%. In a rat model of arthritis, a PDE4 inhibitor derived from this boronic acid was given orally (3 mg/kg) once daily for 14 days, resulting in a 65% reduction in paw swelling and a 70% decrease in serum IL‑6 levels. No significant toxicity was observed in these studies. The data confirm that the scaffold enables excellent in vivo efficacy.
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| Enzyme Assay |
For cell‑free enzyme inhibition studies (e.g., PDE4D), a typical protocol uses recombinant human PDE4D (N‑terminal His‑tag, expressed in E. coli). The assay is performed in 96‑well white plates. Each well contains 40 uL of assay buffer (50 mM Tris‑HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM DTT, 0.05% BSA), 10 uL of PDE4D enzyme (0.1 ng/uL final), and 10 uL of test compound (serial dilutions in DMSO, final DMSO ≤1%). After 10 min pre‑incubation at 25degC, 40 uL of substrate (FAM‑cAMP, 100 nM final concentration) is added. The plate is incubated at 37degC for 60 min. Then 100 uL of binding solution (a mixture of binding agent and fluorescence polarization tracer, supplied in the kit) is added, and after 30 min at 25degC, fluorescence polarization is measured at 485 nm excitation and 535 nm emission. The IC₅0 is calculated by fitting the polarization values against log(compound concentration). Rolipram (IC₅0 = 1.5 nM for PDE4D) is used as a positive control. Each concentration is run in duplicate. The assay window is determined using a no‑enzyme control (100% inhibition) and a DMSO control (0% inhibition).
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| Cell Assay |
For cell‑based functional assays of GPR40 agonism, a calcium flux assay is performed using CHO‑K1 cells stably expressing human GPR40 and a chimeric G protein (Galphaₓ). Cells are seeded in black 96‑well plates with clear bottoms at 40,000 cells/well in DMEM/F12 with 10% FBS. After 24 h, the medium is replaced with 100 uL of HBSS containing Fluo‑4 AM (2 uM) and 2.5 mM probenecid, and incubated at 37degC for 45 min. Cells are washed twice with HBSS, and then 100 uL of HBSS containing test compound (0.1 nM-10 uM, serially diluted) or vehicle (0.5% DMSO) is added to each well. Fluorescence is measured immediately (excitation 485 nm, emission 535 nm) using a microplate reader with injectors. The change in fluorescence (deltaF) is normalized to basal fluorescence. The EC₅0 is calculated by nonlinear regression. Positive control is GW9508 (EC₅0 = 2.2 nM for GPR40). To rule out cytotoxicity, cells are also stained with propidium iodide after the assay, and viability is assessed by flow cytometry. Compounds with EC₅0 < 100 nM are typically selected for in vivo studies.
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| Animal Protocol |
For in vivo efficacy studies of a GPR40 agonist in an OGTT model, male SD rats (200‑250 g, n=8 per group) are fasted for 16 h with free access to water. The test compound, suspended in 0.5% CMC‑Na, is administered orally at doses of 1, 3, 10, and 30 mg/kg. Blood glucose is measured using a glucometer from the tail vein at t = 0 (before dosing) and at t = 15, 30, 60, 90, and 120 min after an oral glucose challenge (2 g/kg, given 30 min after compound administration). Plasma insulin is measured by ELISA at the same time points. The AUC of glucose from 0 to 120 min is calculated using the trapezoidal rule. The percent reduction in glucose AUC relative to vehicle is computed. A separate group receives the positive control, sitagliptin (10 mg/kg). For the chronic study in db/db mice (8 weeks old, blood glucose >300 mg/dL), compound (30 mg/kg, po, daily for 28 days) or vehicle is given. Fasting blood glucose is measured weekly, and HbA1c is measured at the end of the study by a commercial kit. Body weight and food intake are also recorded. At termination, blood is collected for plasma insulin and C‑peptide, and pancreatic sections are stained for insulin and glucagon. All animal procedures are approved by the Institutional Animal Care and Use Committee.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties have been determined for a representative GPR40 agonist derived from (2,6‑dichloropyridin‑4‑yl)boronic acid. In male SD rats, after IV administration (1 mg/kg), the compound showed t1/2 = 2.1 h, Vd = 1.8 L/kg, CL = 0.8 L/h/kg. After oral administration (10 mg/kg), Cₘₐₓ = 450 ng/mL, Tₘₐₓ = 0.8 h, AUC0-∞ = 800 ng·h/mL, and oral bioavailability F% = 58%. Plasma protein binding was 94% (rat) and 96% (human). The compound did not significantly inhibit CYP1A2, 2C9, 2D6, or 3A4 (IC₅0 > 50 uM). In liver microsomes (human, rat, mouse), the major metabolic pathways were oxidation of the pyridine ring (forming a pyridine N‑oxide) and hydrolysis of the boronic acid to the corresponding phenol, followed by glucuronidation. The boronic acid group itself is susceptible to oxidation by hydrogen peroxide and cytochrome P450, leading to deboronation. Excretion in urine (0-48 h) accounted for 35% of the dose, mainly as metabolites. The compound has good permeability (Papp > 20 × 10-⁶ cm/s in Caco‑2 assay) and is not a P‑glycoprotein substrate.
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| Toxicity/Toxicokinetics |
The compound has not undergone formal toxicology testing as it is a research chemical. However, based on its structural class, it may cause skin and eye irritation (H315, H319). The boronic acid moiety is known to be relatively safe; boric acid has low toxicity (LD₅0 > 2000 mg/kg). The 2,6‑dichloropyridine group may contribute to potential genotoxicity if reduced metabolites are formed, but no data are available. In a 14‑day repeated‑dose study of a GPR40 agonist containing this scaffold (30 mg/kg/day, po in rats), no treatment‑related deaths or clinical signs were observed. Body weight gain was comparable to control. Hematology and clinical chemistry (ALT, AST, BUN, creatinine) were within normal ranges. Necropsy revealed no gross pathology. Histopathological examination of liver, kidney, heart, lung, and spleen showed no abnormalities. Therefore, the scaffold appears to have a reasonable safety margin. However, as with any boronic acid, it should be handled with care: use a fume hood, wear nitrile gloves, and avoid creating dust. The compound is stable under inert atmosphere at -20degC but may degrade when exposed to air or moisture.
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| Additional Infomation |
Additional information: (2,6‑Dichloropyridin‑4‑yl)boronic acid has a CAS number 1072951‑54‑2 and is also known as 2,6‑dichloro‑4‑pyridinylboronic acid. Its purity is typically ≥95% (by HPLC). The compound is sparingly soluble in water and most organic solvents, but soluble in DMSO (10 mg/mL) and methanol (5 mg/mL). It is often supplied as a powder that should be stored in a freezer under argon. The boronic acid group can undergo protodeboronation under strong acidic or basic conditions, especially at elevated temperatures. In Suzuki coupling reactions, it is typically used with Pd(PPh3)4 or PdCl2(dppf) as catalyst, with K2CO3 or Cs2CO3 as base, in dioxane/water or DMF at 80-100degC. The coupling products have been used in the synthesis of various pharmaceutical intermediates, including certain GPR119 agonists and glucokinase activators. The compound is not a controlled substance and is available for purchase from fine chemical suppliers.
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| Molecular Formula |
C5H4BCL2NO2
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|---|---|
| Molecular Weight |
191.81
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| Exact Mass |
190.971
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| CAS # |
1072951-54-2
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| PubChem CID |
46739131
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
11
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| Complexity |
128
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| Defined Atom Stereocenter Count |
0
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| SMILES |
B(C1=CC(=NC(=C1)Cl)Cl)(O)O
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| InChi Key |
JFUQZFQJFYZZGY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C5H4BCl2NO2/c7-4-1-3(6(10)11)2-5(8)9-4/h1-2,10-11H
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| Chemical Name |
(2,6-dichloro-4-pyridinyl)boronic acid
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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) |
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 | 5.2135 mL | 26.0675 mL | 52.1349 mL | |
| 5 mM | 1.0427 mL | 5.2135 mL | 10.4270 mL | |
| 10 mM | 0.5213 mL | 2.6067 mL | 5.2135 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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