H1 receptor ( Ki = 9.7 nM )
Histamine H1 receptor (IC50 = 20.3 nmol/L; Ki = 9.7 nmol/L)
Alpha-1D adrenoceptor (IC50 = 7.76 μmol/L; Ki = 3.81 μmol/L)
Dopamine D3 receptor (IC50 = 3.43 μmol/L; Ki = 1.16 μmol/L)
Sigma σ1 receptor (IC50 = 5.46 μmol/L; Ki = 2.3 μmol/L)[1]

SUN-1334H significantly inhibits histamine-induced contractions of isolated guinea-pig ileum with an IC50 (half the maximal inhibitory concentration) of 0.198 μM. SUN-1334H does not alter hERG K⁺-currents in CHO-K1/hERG cells at concentrations up to 100 μM[1]. SUN-1334H, cetirizine and hydroxyzine cause comparable inhibition of NLF leukocytes, IL-4 and total protein concentrations[2].

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SUN-1334H exhibited potent and selective histamine H1 receptor antagonistic activity in recombinant human receptor binding assays (IC50 = 20.3 nmol/L, Ki = 9.7 nmol/L). It showed no or insignificant affinity (generally <50% inhibition at 10 μmol/L) for a wide panel of other receptors, ion channels, and enzymes, including histamine H2, H3, H4 receptors, muscarinic receptors, serotonin receptor subtypes, GABA receptors, glutamate receptors, adrenergic receptors, dopamine receptors (except D3), opioid receptors, and cytochrome P450 (CYP) isozymes (CYP1A2, 2C19, 2C9, 2D6, 3A4).[1]
In functional assays using isolated tissues, SUN-1334H potently inhibited histamine-induced contractions of guinea pig ileum in a concentration-dependent manner (IC50 = 0.198 μmol/L). In contrast, it had no significant effect (IC50 > 100 μmol/L) on contractions induced by carbachol (muscarinic agonist), BaCl2, serotonin (rat fundus), or norepinephrine (rat anococcygeus muscle), nor on the histamine-induced positive chronotropic effect in guinea pig right atrium (H2-mediated).[1]

SUN-1334H effectively suppresses histamine and effectively prevents histamine-induced bronchospasm for 24 hours after oral administration.Ovalbumin-induced rhinitis in guinea pigs and -induced skin wheal in beagle dogs[1]. SUN-1334H exhibits a significant reduction in both passive and active cutaneous anaphylactic reactions in skin allergy models. Desloratadine and fexofenadine have no discernible effects in SUN-1334H models of central nervous system side effects[2].

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Oral administration of SUN-1334H (15-100 μg/kg) dose-dependently inhibited histamine-induced bronchoconstriction in conscious guinea pigs, with complete attenuation of asphyxia and convulsions at doses ≥50 μg/kg. A single oral dose (300 μg/kg) provided complete protection against histamine challenge 24 hours post-administration, indicating a long duration of action.[1]
In beagle dogs, oral SUN-1334H (0.35 mg/kg) rapidly and potently inhibited histamine-induced skin wheal formation, with significant inhibition visible within 0.5 hours, complete suppression from 1 to >10 hours, and >40% inhibition remaining at 24 hours. Its efficacy was superior to cetirizine HCl, desloratadine, and fexofenadine HCl at several time points.[1]
In ovalbumin-sensitized guinea pigs, oral SUN-1334H (1-10 mg/kg) dose-dependently inhibited allergic rhinitis symptoms, including sneezing, nose rubbing, lacrimation, increases in intranasal pressure (INP), and nasal vascular permeability (dye leakage). At 10 mg/kg, it completely blocked ovalbumin-induced sneezing and nose rubbing.[1]

In vitro receptor and enzyme binding assays were conducted using recombinant receptor or enzyme systems. Membranes expressing the target receptors were incubated with a relevant radioligand, SUN-1334H, and buffer. For enzyme inhibition assays, enzyme-expressing systems were incubated with substrate, buffer, and SUN-1334H. Primary screening was performed at a concentration of 10 μmol/L. If inhibition exceeded 50%, the half-maximal inhibitory concentration (IC50) was determined. Results were expressed as percent inhibition of binding or enzyme activity. Specific details for numerous receptor subtypes and enzymes are listed in the provided tables.[1]
The effect of SUN-1334H on human ether-à-go-go related gene (hERG) potassium currents was assessed using CHO-K1 cells stably transfected with the hERG gene. Cells were voltage-clamped in the whole-cell configuration. After obtaining control recordings, cells were exposed to SUN-1334H (0.001-100 μmol/L) or a reference compound. The amplitude of the tail currents was measured and analyzed.[1]

The assay for hERG K+ current inhibition was performed in CHO-K1/hERG transfected cells. Cells were plated on coverslips in a perfusion chamber, maintained at constant temperature, and superfused with control buffer. Whole-cell patch-clamp recordings were performed. After control recordings, cells were exposed to increasing concentrations of SUN-1334H (0.001 to 100 μmol/L). The amplitude of the tail current (hERG K+ current) was measured and compared to baseline.[1]

For histamine-induced bronchoconstriction in conscious guinea pigs, animals were orally administered SUN-1334H (15-100 μg/kg), cetirizine HCl (50 μg/kg), or vehicle 1 hour before challenge. They were placed in whole-body plethysmographs and exposed to histamine aerosol (100-400 μg/mL) for 3 minutes. Bronchoconstriction was measured as enhanced pause (Penh) over 10 minutes. For duration studies, a 300 μg/kg dose was given 24 hours before a 200 μg/mL histamine challenge.[1]
For histamine-induced skin wheal in beagle dogs, wheals were induced by intradermal histamine on the shaved abdomen. Baseline wheal area was measured (0-hour). Dogs were orally given SUN-1334H (0.35 mg/kg), desloratadine (0.35 mg/kg), cetirizine HCl (0.35 mg/kg), or fexofenadine HCl (10 mg/kg). Wheals were re-induced and measured at various time points post-dose. Inhibition was calculated relative to the 0-hour area.[1]
For ovalbumin-induced allergic rhinitis in guinea pigs, animals were sensitized by intraperitoneal injections of ovalbumin with adjuvant on days 0, 7, 14, and 21. One week after the last sensitization, drugs or vehicle were administered orally. One hour later, animals were challenged intranasally with ovalbumin solution. Sneezes were counted for 2 hours. For intranasal pressure (INP) and permeability measurements, sensitized, anesthetized guinea pigs were used. INP was recorded via a nasopharyngeal cannula connected to a pressure transducer before and after ovalbumin aerosol challenge. For vascular permeability, Evans blue dye was injected intravenously, and the nasal cavity was perfused; dye leakage into the perfusate was quantified spectrophotometrically.[1]
Cardiovascular safety was assessed in anesthetized guinea pigs. Animals were anesthetized, and ECG leads were placed. SUN-1334H (15 mg/kg), terfenadine (7 mg/kg), or vehicles were administered intravenously. ECG was recorded continuously for 1 hour.[1]
Cardiovascular safety was also assessed in conscious telemetrized beagle dogs. Animals were surgically implanted with telemetry transmitters. After recovery, each dog received oral vehicle and three doses of SUN-1334H (15, 50, 100 mg/kg) in a crossover design with washout periods. ECG and blood pressure were recorded before and for 24 hours after dosing.[1]
Central nervous system (CNS) safety was assessed using a functional observational battery (FOB) in rats. Rats were orally administered SUN-1334H (32, 191, 637 mg/kg), reference drugs, or vehicle. A blinded observer assessed behavior, reactivity, locomotor activity, reflexes, and body temperature at 1, 2, 4, and 24 hours post-dose.[1]
Pentobarbital-induced sleeping time was measured in mice. One hour after oral administration of SUN-1334H, reference antihistamines, or vehicle, pentobarbital was injected subcutaneously. The time from loss to recovery of righting reflex was recorded.[1]
Effect on pentylenetetrazol-induced convulsions was tested in mice. Two hours after oral administration of SUN-1334H (300 mg/kg), fexofenadine HCl (300 mg/kg), caffeine (100 mg/kg), or vehicle, pentylenetetrazol was injected subcutaneously. Incidence of clonic or tonic seizures was recorded.[1]
Effect on intestinal transit was assessed in rats. SUN-1334H (19 mg/kg), atropine sulfate (10 mg/kg), or vehicle were administered orally. A charcoal meal was given 1 hour (atropine) or 2 hours (SUN-1334H/vehicle) later. After 15 minutes, animals were sacrificed, and the distance traveled by the charcoal meal in the small intestine was measured and expressed as a percentage of total intestinal length.[1]

At concentrations up to 100 μmol/L, SUN-1334H had no significant effect on hERG K+ currents in CHO-K1 cells. [1] In anesthetized guinea pigs, intravenous administration of high doses of SUN-1334H (15 mg/kg) did not significantly alter heart rate, QT interval, QTc interval (Bazett and Fridricia intervals), RR interval, or QRS interval, nor did it alter electrocardiogram morphology. In contrast, intravenous administration of terfenadine (7 mg/kg) caused significant QT interval prolongation and torsades de pointes ventricular tachycardia. [1] In awake telemetry dogs, oral doses of SUN-1334H up to 100 mg/kg had no significant effect on arterial blood pressure or QTc interval (Fridericia interval). Dose of 50 and 100 mg/kg caused transient and significant increases in heart rate over 2–6 hours, but this was not observed after 24 hours. There was no effect on ventricular repolarization. [1]
In rats, oral doses of up to 637 mg/kg of SUN-1334H (far above the effective dose) had no effect on body temperature or most behaviors in the FOB. The only observable effect at the 637 mg/kg dose was somnolence. [1]
SUN-1334H (oral dose of 100 mg/kg) did not enhance pentobarbital-induced sleep duration in mice, unlike loratadine, which significantly prolonged sleep duration. [1]
SUN-1334H (oral dose of 300 mg/kg) did not modulate the incidence or pattern of pentylenetetrazol-induced seizures in mice. [1]
SUN-1334H (oral administration of 19 mg/kg) did not affect the intestinal transport of activated charcoal meals in rats, indicating that it has no anticholinergic effect on intestinal motility. [1]
SUN-1334H showed low activity against major cytochrome P450 isoenzymes (CYP1A2, 2C19, 2C9, 2D6, 3A4) in enzyme profile analysis, indicating that the possibility of pharmacokinetic drug interactions through this pathway is low. [1]

[1]. Preclinical efficacy and safety pharmacology of SUN-1334H, a potent orally active antihistamine agent. Drugs R D. 2008;9(2):93-112.

[2]. Characterization of anti-inflammatory properties and evidence for no sedation liability for the novel antihistamine SUN-1334H. Int Arch Allergy Immunol. 2010;151(1):56-69.

SUN-1334H is the dihydrochloride of 4-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]-(E)-but-2-enoxy]acetic acid. It is a non-chiral, water-soluble molecule. [1] It is a potent, orally effective, and highly selective histamine H1 receptor antagonist with long-acting activity in preclinical models. [1] It is currently undergoing clinical development for the treatment of allergic diseases. As of the time of this writing, a Phase II clinical trial is underway in the United States. [1] The study was funded by Sun Pharma Advanced Research Company Limited, to which all authors are employed. [1]

C23H28CL2F2N2O3

489.382831573486

488.144

C, 56.45; H, 5.77; Cl, 14.49; F, 7.76; N, 5.72; O, 9.81

607736-84-5

607737-00-8

69509032

Light yellow to yellow solid powder

3

7

9

32

517

0

O=C(O)COC/C=C/CN1CCN(C(C2=CC=C(F)C=C2)C3=CC=C(F)C=C3)CC1.[H]Cl.[H]Cl

KAQMKGKFTBFMGE-SEPHDYHBSA-N

InChI=1S/C23H26F2N2O3.2ClH/c24-20-7-3-18(4-8-20)23(19-5-9-21(25)10-6-19)27-14-12-26(13-15-27)11-1-2-16-30-17-22(28)29;;/h1-10,23H,11-17H2,(H,28,29);2*1H/b2-1+;;

2-[(E)-4-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]but-2-enoxy]acetic acid;dihydrochloride

SUN-1334H; SUN1334H; SUN 1334H

2934.99.9001

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, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)