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| Targets |
DHODH-IN-5 targets human dihydroorotate dehydrogenase (DHODH), a class 2 mitochondrial enzyme that catalyzes the fourth and rate-limiting step of de novo pyrimidine biosynthesis, converting dihydroorotate to orotate. DHODH is essential for the proliferation of rapidly dividing cells, including activated lymphocytes and virus-infected cells, as they require sufficient pyrimidine nucleotides for DNA and RNA synthesis. By inhibiting DHODH, the compound depletes intracellular pyrimidine pools, thereby limiting viral replication and cellular proliferation. The high potency (pIC₅₀ 7.8) indicates strong binding affinity to the human enzyme. DHODH-IN-5's antiviral activity against measles virus (pMIC₅₀ 8.8) highlights its therapeutic potential for viral infections that depend on host pyrimidine biosynthesis.
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| ln Vitro |
In vitro, DHODH-IN-5 demonstrates potent inhibition of human recombinant DHODH with a pIC₅₀ of 7.8, corresponding to an IC₅₀ of approximately 16 nM. The compound exhibits significant antiviral activity against measles virus with a pMIC₅₀ of 8.8, indicating potent inhibition of viral replication in cell-based assays. The antiviral effect is attributed to the depletion of intracellular pyrimidine nucleotide pools through DHODH inhibition, which restricts viral RNA synthesis and replication. Cytotoxicity studies may be performed in parallel to determine the selectivity index of the compound. The compound's activity is concentration-dependent, with efficacy observed at nanomolar to low micromolar concentrations. These in vitro data support the development of DHODH inhibitors as broad-spectrum antiviral agents.
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| ln Vivo |
In vivo data for DHODH-IN-5 are not extensively reported in the available literature. As a potent DHODH inhibitor with antiviral activity, the compound would be expected to demonstrate efficacy in animal models of measles virus infection or other DHODH-dependent viral diseases. DHODH inhibitors have been studied in various preclinical models for their immunomodulatory and antiviral properties. The compound's in vivo pharmacokinetic and pharmacodynamic profiles would determine its suitability for therapeutic development. Based on its physicochemical properties (molecular weight 364.44, DMSO solubility 125 mg/mL), DHODH-IN-5 may be formulated for in vivo administration using appropriate vehicles such as DMSO/PEG300/Tween 80/saline mixtures. Further studies are needed to establish its in vivo efficacy, safety, and dosing regimens.
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| Enzyme Assay |
In vitro enzyme/receptor binding (non-cellular) assays for DHODH-IN-5 involve measuring inhibition of human recombinant DHODH enzymatic activity. The assay typically uses a colorimetric or fluorometric method to detect the conversion of dihydroorotate to orotate coupled with the reduction of the electron acceptor (e.g., 2,6-dichloroindophenol, DCIP). The enzyme is incubated with varying concentrations of the compound, substrate (dihydroorotate), and coenzyme (ubiquinone or decylubiquinone) in assay buffer (typically 50 mM Tris-HCl, pH 8.0, with 0.1% Triton X-100). The reaction is monitored spectrophotometrically by following the decrease in absorbance at 600 nm (DCIP reduction) or by measuring the production of orotate using HPLC. IC₅₀ values are calculated from concentration-response curves. The pIC₅₀ of 7.8 indicates high potency.
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| Cell Assay |
In vitro cellular experiments with DHODH-IN-5 are performed using virus-infected cell lines to assess antiviral activity. Measles virus replication assays are typically conducted in Vero cells or other susceptible cell lines. Cells are cultured in appropriate medium (e.g., DMEM with 10% FBS) and infected with measles virus at a suitable multiplicity of infection (MOI). Following virus adsorption, cells are treated with varying concentrations of DHODH-IN-5 for 24-72 hours. Viral replication is quantified by measuring viral RNA levels using RT-qPCR, viral protein expression by Western blot or immunofluorescence, or viral titers by plaque assay or TCID₅₀. The pMIC₅₀ of 8.8 indicates potent inhibition of viral replication. Cytotoxicity is assessed in parallel using MTT or CellTiter-Glo assays to determine the selectivity index. Cells are maintained at 37°C in 5% CO₂.
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| Animal Protocol |
In vivo animal studies with DHODH-IN-5 have not been extensively reported. For DHODH inhibitors in general, in vivo efficacy studies are typically performed in mouse models of viral infection or autoimmune disease. In antiviral studies, mice are infected with the target virus (e.g., measles virus in immunocompromised or transgenic mouse models) and treated with the compound via oral, intraperitoneal, or intravenous administration at various doses. Efficacy is assessed by survival rates, viral burden in target organs (lung, spleen, brain), weight loss, and clinical scores. Pharmacodynamic markers such as uridine or orotate levels in plasma or tissues may be measured to confirm target engagement. For immunomodulatory applications, DHODH inhibitors are studied in models of rheumatoid arthritis, multiple sclerosis, or graft-versus-host disease.
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| ADME/Pharmacokinetics |
Comprehensive pharmacokinetic data for DHODH-IN-5 are not extensively reported in the available literature. The compound has a molecular weight of 364.44 and is soluble in DMSO at 125 mg/mL (342.99 mM), suggesting reasonable potential for formulation and administration. As a DHODH inhibitor, it is expected to have good cellular permeability due to its lipophilic properties. Storage recommendations: powder at -20°C; stock solutions at -80°C for 6 months or -20°C for 1 month. For in vivo administration, the compound can be formulated using vehicles such as DMSO, PEG300, Tween 80, and saline. Detailed pharmacokinetic parameters including half-life, clearance, bioavailability, and tissue distribution require further investigation from primary research publications.
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| Toxicity/Toxicokinetics |
Toxicological information for DHODH-IN-5 is not extensively detailed in the available literature. As a potent enzyme inhibitor with antiviral activity, the compound should be handled as a research chemical with appropriate safety precautions. Standard safety guidelines for handling potent pharmaceutical compounds apply, including use of personal protective equipment (gloves, safety goggles, lab coat), working in a well-ventilated area, and proper chemical waste disposal. The compound is intended for research use only and is not approved for human therapeutic use. Cytotoxicity studies in cell-based assays help establish the therapeutic window and selectivity index of the compound. The compound is supplied as a solid powder with purity ≥98% and should be stored at -20°C.
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| References | |
| Additional Infomation |
DHODH-IN-5 (CAS 1644156-56-8) is a potent human dihydroorotate dehydrogenase (DHODH) inhibitor with a pIC₅₀ of 7.8 for human recombinant DHODH. The compound has molecular formula C₂₁H₂₄N₄O₂ and molecular weight 364.44. It demonstrates antiviral activity against measles virus with a pMIC₅₀ of 8.8. DHODH-IN-5 is supplied as a solid powder with purity ≥98% and is soluble in DMSO at 125 mg/mL (342.99 mM). The compound belongs to the class of 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives and was described in the Journal of Medicinal Chemistry in 2015. Storage recommendations: powder at -20°C; stock solutions at -80°C for 6 months or -20°C for 1 month. DHODH-IN-5 is exclusively for research purposes and is not approved for clinical use in humans.
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| Molecular Formula |
C21H24N4O2
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| Molecular Weight |
364.440864562988
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| Exact Mass |
364.189
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| CAS # |
1644156-56-8
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| PubChem CID |
118430507
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| Appearance |
White to off-white solid powder
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| LogP |
3.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
27
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| Complexity |
473
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C(C)C)C1C(C(C2C=CC=CC=2)O)=C(C)N(C2=NC=C(C=N2)C2CC2)N=1
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| InChi Key |
BSNKBAPMWCMENP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H24N4O2/c1-13(2)27-20-18(19(26)16-7-5-4-6-8-16)14(3)25(24-20)21-22-11-17(12-23-21)15-9-10-15/h4-8,11-13,15,19,26H,9-10H2,1-3H3
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| Chemical Name |
[1-(5-cyclopropylpyrimidin-2-yl)-5-methyl-3-propan-2-yloxypyrazol-4-yl]-phenylmethanol
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| Synonyms |
DHODHIN5; DHODH IN 5
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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 : ~125 mg/mL (~342.99 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 6.25 mg/mL (17.15 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 62.5 mg/mL clear DMSO stock solution to 900 μL 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 | 2.7439 mL | 13.7197 mL | 27.4394 mL | |
| 5 mM | 0.5488 mL | 2.7439 mL | 5.4879 mL | |
| 10 mM | 0.2744 mL | 1.3720 mL | 2.7439 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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