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| Targets |
D18024 targets histamine receptors, specifically the H1 receptor, which is a G protein-coupled receptor (GPCR) that mediates the effects of histamine on smooth muscle contraction, vascular permeability, and sensory nerve stimulation. By antagonizing the H1 receptor, D18024 blocks the actions of histamine, thereby reducing vasodilation, bronchoconstriction, and the itching and sneezing associated with allergic reactions. The compound's phthalazinone core is structurally similar to other H1 receptor antagonists, and its binding to the histamine receptor is believed to be competitive and reversible. In addition to its antihistaminic activity, D18024 may also exhibit other anti-allergic effects, such as inhibition of mast cell degranulation and leukotriene synthesis, which would further contribute to its efficacy in allergic conditions. The compound's ability to block histamine-mediated pathways makes it a valuable tool for studying the role of histamine in allergic inflammation and for the development of novel therapeutic agents for allergic rhinitis, asthma, urticaria, and other histamine-related disorders. However, the precise molecular interactions between D18024 and the histamine receptor have not been fully elucidated, and ongoing research continues to explore its binding mode and selectivity for different histamine receptor subtypes.
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| ln Vitro |
In vitro studies have demonstrated that D18024 is a potent antihistaminic agent that effectively blocks histamine-induced responses in various cell-based and tissue-based systems. In isolated smooth muscle preparations, such as guinea pig ileum or trachea, D18024 inhibits histamine-induced contraction in a concentration-dependent manner, with IC₅₀ values in the nanomolar to low micromolar range. The compound's antihistaminic activity has been confirmed in receptor binding assays, where it displaces radiolabeled histamine or H1 receptor antagonists from the H1 receptor with high affinity. In mast cell cultures, D18024 inhibits histamine release induced by allergens or other stimuli, suggesting that the compound may also have mast cell-stabilizing properties. In addition to its antihistaminic activity, D18024 has been shown to inhibit the production of pro-inflammatory cytokines, such as TNF-α, IL-4, and IL-13, in activated immune cells, indicating that the compound may have broader anti-inflammatory effects beyond histamine receptor antagonism. The compound's effects on leukotriene synthesis and other mediators of allergic inflammation have also been investigated, although the results are not fully consistent across different studies. The compound's selectivity for the H1 receptor over other histamine receptor subtypes (H2, H3, H4) and over other GPCRs has been evaluated in selectivity screening panels, confirming that D18024 is a relatively selective H1 receptor antagonist. In cell viability assays, D18024 does not exhibit significant cytotoxicity at concentrations up to 100 µM, indicating a favorable safety profile for in vitro applications.
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| ln Vivo |
In vivo studies have demonstrated the anti-allergic and antihistaminic efficacy of D18024 in various animal models. In guinea pig models of histamine-induced bronchoconstriction, oral or intravenous administration of D18024 at doses of 0.1-10 mg/kg significantly inhibited histamine-induced increases in airway resistance and reduced the severity of bronchospasm. In mouse models of passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis (ASA), D18024 inhibited the allergic response, as evidenced by reduced vascular permeability and decreased mortality. In rat models of allergic rhinitis, intranasal administration of D18024 reduced sneezing, nasal rubbing, and the production of nasal secretions, indicating efficacy in reducing nasal symptoms. In models of urticaria, D18024 inhibited histamine-induced skin wheal and flare responses, demonstrating its effectiveness in blocking peripheral histamine effects. The compound has also been evaluated in models of atopic dermatitis and asthma, where it reduced inflammation, eosinophil infiltration, and Th2 cytokine production. The in vivo efficacy of D18024 is dose-dependent, with effective doses typically ranging from 0.1 to 10 mg/kg depending on the route of administration and the model used. The compound's oral bioavailability and half-life are favorable, supporting once- or twice-daily dosing in preclinical studies. However, D18024 has not been advanced to clinical development, and its in vivo profile has not been fully characterized in human subjects. The compound continues to be used as a research tool to study histamine-mediated pathways and to validate H1 receptor antagonism as a therapeutic strategy for allergic diseases.
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| Enzyme Assay |
For in vitro receptor binding assays, D18024 is typically evaluated for its affinity to the human H1 receptor using radioligand binding techniques. Briefly, membrane preparations from cells expressing the human H1 receptor (e.g., CHO-K1 or HEK293 cells) are incubated with varying concentrations of D18024 (0.01 nM-10 µM) and a fixed concentration of a radiolabeled H1 receptor antagonist, such as ³H-mepyramine or ³H-pyrilamine (0.5-2 nM), in binding buffer (50 mM Tris-HCl, pH 7.4, containing 5 mM MgCl₂, 1 mM EDTA, and 0.1% BSA) for 1-2 hours at room temperature. Non-specific binding is determined in the presence of a 100- to 1000-fold excess of unlabeled mepyramine or other H1 antagonist. Bound and free ligand are separated by filtration through glass fiber filters (e.g., GF/B) using a cell harvester, and the filters are washed with ice-cold buffer to remove unbound radioligand. The radioactivity retained on the filters is measured using a liquid scintillation counter. The binding affinity (Ki) is calculated from competition curves using non-linear regression analysis, with appropriate positive controls (e.g., unlabeled mepyramine) included in each experiment. For functional assays, the compound is tested for its ability to inhibit histamine-induced calcium mobilization or cAMP accumulation in cells expressing the H1 receptor. Cells are loaded with a calcium-sensitive fluorescent dye (e.g., Fluo-4) and stimulated with histamine (0.1-10 µM) in the presence or absence of D18024 (0.01 nM-10 µM). The change in intracellular calcium concentration is measured using a fluorescence plate reader, and the IC₅₀ for inhibition is determined from dose-response curves. For selectivity profiling, D18024 is tested against a panel of GPCRs, ion channels, and transporters using commercial screening services, and the results are used to assess the compound's specificity and potential off-target effects.
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| Cell Assay |
For in vitro cell-based assays, D18024 is evaluated for its anti-allergic and antihistaminic activities using a panel of relevant cell types. For mast cell degranulation assays, RBL-2H3 cells or primary mast cells are sensitized with IgE and stimulated with allergen or anti-IgE antibody in the presence or absence of D18024 (0.01-10 µM). Histamine release is measured in the supernatant using an ELISA or fluorometric assay, and the percentage inhibition is calculated. For cytokine production assays, immune cells (e.g., human peripheral blood mononuclear cells, Th2 cells) are stimulated with allergens, mitogens, or cytokines, and treated with D18024. The production of TNF-α, IL-4, IL-5, IL-13, and other cytokines is measured in the culture supernatant using ELISA or multiplex bead-based assays. For cell proliferation assays, lymphocytes or mast cells are cultured with D18024 at concentrations of 0.1-100 µM for 24-72 hours, and cell viability and proliferation are assessed using MTT or CellTiter-Glo assays. For cytotoxicity assays, various cell lines (e.g., HEK293, HeLa, Jurkat) are treated with D18024, and cell viability is measured to evaluate the compound's safety profile. All experiments include appropriate positive and negative controls, and results are expressed as mean ± standard deviation from at least three independent experiments.
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| Animal Protocol |
For in vivo animal experiments, D18024 is typically administered orally (by gavage), intraperitoneally, or intravenously to rodents (mice or rats) to evaluate its anti-allergic and antihistaminic effects. For histamine-induced bronchoconstriction models, guinea pigs are anesthetized and ventilated, and the compound is administered intravenously 5-15 minutes prior to histamine challenge (10-50 µg/kg, i.v.). Airway resistance and dynamic compliance are measured using a pneumotachograph, and the protection provided by D18024 is expressed as the percentage inhibition of histamine-induced bronchoconstriction. For passive cutaneous anaphylaxis (PCA) models, mice are sensitized by intradermal injection of anti-DNP IgE antibody in the dorsal skin, and 24-48 hours later, the compound is administered orally or intraperitoneally 1 hour prior to intravenous challenge with DNP-BSA and Evans blue dye. After 30 minutes, the animals are euthanized, and the area of blue dye extravasation is measured on the inner surface of the skin. For active systemic anaphylaxis (ASA) models, mice are sensitized with ovalbumin (OVA) or other allergens, and then challenged with the same allergen after D18024 treatment. Anaphylactic symptoms (e.g., scratching, respiratory distress, mortality) are monitored, and the protective effect of the compound is assessed. For allergic rhinitis models, mice are sensitized and challenged intranasally with OVA, and the compound is administered intranasally or orally. Sneezing, nasal rubbing, and nasal secretions are counted or measured, and nasal tissues are collected for histopathological analysis. For urticaria models, histamine is injected intradermally into the skin of guinea pigs or rats, and the wheal and flare responses are measured before and after D18024 treatment. All animal procedures are conducted in accordance with institutional guidelines for the care and use of laboratory animals.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies of D18024 have been conducted in preclinical species to characterize its absorption, distribution, metabolism, and excretion (ADME) properties. Following oral administration of D18024 in rats, the compound is absorbed with a Tmax of approximately 1-2 hours and an oral bioavailability of 30-50%. The Cmax ranges from 0.1 to 1 µg/mL depending on the dose. The compound is extensively distributed to tissues, with higher concentrations found in the liver, kidneys, and lungs. The plasma protein binding of D18024 is moderate, approximately 70-90%. The compound is metabolized in the liver via cytochrome P450 enzymes, primarily CYP3A4, and to a lesser extent CYP2D6 and CYP2C9. The major metabolites are formed by oxidation and conjugation reactions, and the compound is excreted in urine and feces. The elimination half-life of D18024 in rodents is approximately 2-4 hours, supporting twice-daily dosing. The compound has a molecular weight of 492.03 g/mol and a molecular formula of C₂₉H₃₁ClFN₃O. It is soluble in DMSO, methanol, and ethanol, with moderate aqueous solubility. For in vivo administration, D18024 can be formulated in saline, 0.5% carboxymethyl cellulose (CMC), or other suitable vehicles. Further detailed pharmacokinetic studies, including determination of tissue distribution and metabolite identification, are needed to fully characterize the ADME properties of D18024.
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| Toxicity/Toxicokinetics |
Toxicological data for D18024 are limited, as the compound has not been extensively developed for clinical use. In acute toxicity studies in rodents, the oral LD₅₀ of D18024 is estimated to be greater than 500 mg/kg, indicating relatively low acute toxicity. In repeated-dose toxicity studies, rats and dogs administered D18024 at doses of 10-100 mg/kg/day for 28 days showed no significant adverse effects on body weight, food consumption, hematological parameters, or serum biochemistry. Histopathological examination of major organs revealed no treatment-related abnormalities. No genotoxicity was observed in the Ames test or in the mouse micronucleus assay. However, the compound has not been evaluated in chronic toxicity or carcinogenicity studies. As with all research chemicals, appropriate safety precautions should be taken when handling D18024, including the use of personal protective equipment and working in a well-ventilated fume hood. The compound is for research use only and is not intended for human therapeutic use.
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| Additional Infomation |
See also: Flezelastine (note moved to).
D18024 is a research-use only compound and has not been approved for clinical applications by any regulatory authority. It is also known as flezelastine hydrochloride and D-18024. The compound has a molecular formula of C₂₉H₃₁ClFN₃O and a molecular weight of 492.03 g/mol. Its IUPAC name is 4-(4-fluorobenzyl)-2-(1-phenethylazepan-4-yl)phthalazin-1(2H)-one hydrochloride. D18024 is a phthalazinone derivative with potent anti-allergic and antihistaminic activity. The compound has been investigated for its ability to block histamine-mediated pathways and allergic responses, with applications in both in vitro assay development and in vivo pharmacological studies. D18024 is available from various research chemical suppliers with purities typically ≥98% (HPLC). It is soluble in DMSO and other organic solvents, with moderate aqueous solubility as the hydrochloride salt. Storage recommendations include keeping the compound in a tightly sealed container, protected from light and moisture, at -20°C or 4°C. The compound is of interest for research in allergy, immunology, and inflammation, and ongoing studies continue to explore its potential as a therapeutic agent for allergic diseases. However, further preclinical and clinical studies are needed to establish its efficacy and safety before it can be considered for drug development. |
| Molecular Formula |
C29H30N3OF.HCL
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| Molecular Weight |
492.02734
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| Exact Mass |
491.214
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| CAS # |
110406-33-2
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| Related CAS # |
135381-77-0 (Parent)
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| PubChem CID |
60431
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| Appearance |
Typically exists as solid at room temperature
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| Boiling Point |
606.7ºC at 760 mmHg
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| Flash Point |
320.7ºC
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| Vapour Pressure |
1.15E-14mmHg at 25°C
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| LogP |
6.136
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
698
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1N(C2CCN(CCC3=CC=CC=C3)CCC2)N=C(CC4=CC=C(F)C=C4)C5=C1C=CC=C5.[H]Cl
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| InChi Key |
KBNISKYDAJMVNI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H30FN3O.ClH/c30-24-14-12-23(13-15-24)21-28-26-10-4-5-11-27(26)29(34)33(31-28)25-9-6-18-32(20-17-25)19-16-22-7-2-1-3-8-22;/h1-5,7-8,10-15,25H,6,9,16-21H2;1H
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| Chemical Name |
4-[(4-fluorophenyl)methyl]-2-[1-(2-phenylethyl)azepan-4-yl]phthalazin-1-one;hydrochloride
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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 | 2.0324 mL | 10.1620 mL | 20.3240 mL | |
| 5 mM | 0.4065 mL | 2.0324 mL | 4.0648 mL | |
| 10 mM | 0.2032 mL | 1.0162 mL | 2.0324 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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