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Purity: ≥98%
Toreforant (aslo known as JNJ-38518168) is a novel, potent and selective histamine H4 receptor (H4R) antagonist with a Ki at the human receptor of 8.4 ± 2.2 nM and excellent selectivity over other receptors including the other histamine receptors. The compound acts as an antagonist in all species tested and inhibits histamine-induced eosinophil shape change in vitro. Toreforant was anti-inflammatory in mouse models of asthma and arthritis. However, it was not able to inhibit histamine-induced scratching in mice or block neuropathic pain in rats. The lack of effect in these models may be related to low exposure levels in the central nervous system. Preclinical toxicity studies of up to 6 months in rats and 9 months in monkeys indicated an excellent safety profile with the exception of QT prolongation seen in vivo due to inhibition of the human ether-à-go-go-related gene (hERG) channel. Toreforant was studied in phase 1 human clinical studies to assess safety, pharmacokinetics and pharmacodynamics. The compound was well-tolerated at all doses tested and no safety issues were noted in the phase 1 studies with the exception of QT prolongation observed at the highest dose. Toreforant exhibited good pharmacokinetics upon oral dosing with a plasma half-life consistent with once a day dosing. In addition, dose-dependent inhibition of histamine-induced eosinophil shape change was detected suggesting that the H4R was inhibited in vivo
| ln Vitro |
Toreforant works as an antagonist of human H4R in human polymorphonuclear leukocytes by inhibiting histamine-induced shape alterations in human eosinophils and shifting the histamine dose-response curve to the right. Since this measurement is not in equilibrium, pA2 must be calculated carefully. The change in the antagonist's minimum concentration can be used to determine pA2. The resulting pA2 was roughly 7.5, which agreed with the transfection system's findings. Toreforant reduces the effects of histamine in isolated cells, and the experiment may also be run on whole blood. The IC50 values were 296 nM and 780 nM, respectively, when employing 100 nM and 300 nM histamine[1].
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| ln Vivo |
The animals administered 100 mg/kg of toreforant exhibited a decrease in illness severity scores. The score decrease is comparable to that of JNJ 28307474. Toreforant's anti-itching efficacy was assessed using the histamine-induced CD-1 mouse scratching paradigm (n = 5 per group). In contrast to other H4R antagonists, toreforant does not effectively lessen itching caused by histamine. After oral administration to rats, toreforant produced radioactivity that was widely distributed into tissues; however, it was not quantifiable in the medulla, spinal cord, cerebellum, or cerebrum of either Sprague Dawley or Long Evans rats, suggesting that drug-derived radioactivity does not cross the blood-brain barrier. Toreforant and JNJ 39758979, an H4R antagonist that can pass the blood-brain barrier, were used to create a rat neuropathic pain model. Toreforant produced no activity, but JNJ 39758979 was able to dramatically reduce mechanical allodynia induced in a rat spinal nerve ligation model [1].
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| References |
[1]. Robin L Thurmond, Pharmacology and Clinical Activity of Toreforant, a Histamine H4 Receptor Antagonist. Annals of Pharmacology and Pharmaceutics. 21 Jan, 2017
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| Molecular Formula |
C23H32N6
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|---|---|
| Molecular Weight |
392.540384292603
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| CAS # |
952494-46-1
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| SMILES |
CN1CCC(CCCNC2=NC=C(C3=NC4=C(C)C=C(C)C=C4N3)C(C)=N2)CC1
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| InChi Key |
FCRFVPZAXGJLPW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H32N6/c1-15-12-16(2)21-20(13-15)27-22(28-21)19-14-25-23(26-17(19)3)24-9-5-6-18-7-10-29(4)11-8-18/h12-14,18H,5-11H2,1-4H3,(H,27,28)(H,24,25,26)
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| Chemical Name |
5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl- N-[3-(1-methylpiperidin-4-yl)propyl]pyrimidin-2-amine
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| Synonyms |
JNJ-38518168; JNJ 38518168; JNJ38518168
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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 : ~100 mg/mL (~254.75 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.37 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5475 mL | 12.7376 mL | 25.4751 mL | |
| 5 mM | 0.5095 mL | 2.5475 mL | 5.0950 mL | |
| 10 mM | 0.2548 mL | 1.2738 mL | 2.5475 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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