Toreforant (JNJ-38518168)
(Synonyms: JNJ-38518168) 目录号 : GC31220
Toreforant (JNJ-38518168) 是一种有效的选择性组胺 H4 受体 (H4R) 拮抗剂，对人受体的 Ki 值为 8.4 nM。
Cas No.:952494-46-1
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | Mice[1]The ovalbumin mouse asthma model and the collageninduced arthritis model are conducted. Toreforant is dosed orally in 20% hydroxypropyl-β-cyclodextrin. In the collagen-induced arthritis model Toreforant is given orally twice a day starting with the first signs of disease onset around Day 30 and continued for 14 days. CD-1 mice (5 per group) are dosed with vehicle (20% hydroxypropyl-β-cyclodextrin), Toreforant or JNJ 28307474, as a positive control, at 50 mg/kg orally, 60 mins prior to the intra-dermal injection of histamine. Bouts of scratching are recorded over a 20 minute period. In a subsequent experiment mice are orally dosed with Toreforant (100 mg/kg) at 24, 8, 4 and 1 h prior to intra-dermal injection of histamine and similarly monitored. The area at the back of the neck of mice is shaved 24 hours prior to an intra-dermal injection of 20 μL of 100 μg compound 48/80. Both knockout and wild-type mice (five mice per group) are dosed with vehicle, Toreforant (50 mg/kg) or JNJ 28307474 (50 mg/kg), orally, 60 mins prior to the intradermal injection. Bouts of scratching are recorded over a 20 minute period. Terminal (t=80 min) plasma and brain samples are analyzed for drug concentration. Male Sprague-Dawley rats are deeply anesthetized with isoflurane/oxygen inhalational anesthesia [1]. |
References: [1]. Robin L Thurmond, Pharmacology and Clinical Activity of Toreforant, a Histamine H4 Receptor Antagonist. Annals of Pharmacology and Pharmaceutics. 21 Jan, 2017. | |
Toreforant is a potent and selective histamine H4 receptor (H4R) antagonist, with a Ki at the human receptor of 8.4 nM.
In human polymorphonuclear leukocytes, Toreforant inhibits the histamine-induced shape change of human eosinophils and produces a rightward shift in the histamine dose response curves indicating that it is acting as an antagonist of the human H4R in these primary cells. This is not an equilibrium measurement and therefore the calculation of a pA2 is complicated. The pA2 can be estimated using the shift seen the lowest concentration of antagonist. This yields a pA2 of around 7.5 consistent with the results in the transfected system. This assay can also be performed in whole blood and, as for the purified cells, Toreforant is able to inhibit the actions of histamine. The IC50 values are 296 nM and 780 nM when 100 nM and 300 nM histamine are used, respectively[1].
The animals treated with 100 mg/kg toreforant have reduced disease severity scores. The reduction in scores is similar to JNJ 28307474. A model of histamine-induced scratching in CD-1 mice (n=5 per group) is used to judge the anti-pruritic effects of Toreforant. Unlike other H4R antagonists, Toreforant is not efficacious in reducing histamine-mediated pruritus. After oral administration to rats, Toreforant-derived radioactivity is widely distributed into tissues; however, it is not quantifiable in cerebellum, cerebrum, medulla, and spinal cord in either Long Evans or Sprague Dawley rats, suggesting that drug-derived radioactivity does not cross the blood-brain barrier. Neuropathic pain models in rats are conducted with Toreforant and an H4R antagonist that does cross the blood-brain barrier, JNJ 39758979. In a rat spinal nerve ligation model JNJ 39758979 was able to significantly attenuate the mechanical allodynia induced in the model, however Toreforant has no activity[1].
[1]. Robin L Thurmond, Pharmacology and Clinical Activity of Toreforant, a Histamine H4 Receptor Antagonist. Annals of Pharmacology and Pharmaceutics. 21 Jan, 2017.
| Cas No. | 952494-46-1 | SDF | |
| 别名 | JNJ-38518168 | ||
| Canonical SMILES | CN1CCC(CCCNC2=NC=C(C3=NC4=CC(C)=CC(C)=C4N3)C(C)=N2)CC1 | ||
| 分子式 | C23H32N6 | 分子量 | 392.54 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
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 | 5.095 mL |
| 10 mM | 0.2548 mL | 1.2738 mL | 2.5475 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Clinical Development of Histamine H4 Receptor Antagonists
The discovery of the histamine H4 receptor (H4R) provided a new avenue for the exploration of the physiological role of histamine, as well as providing a new drug target for the development of novel antihistamines. The first step in this process was the identification of selective antagonists to help unravel the pharmacology of the H4R relative to other histamine receptors. The discovery of the selective H4R antagonist JNJ 7777120 was vital for showing a role for the H4R in inflammation and pruritus. While this compound has been very successful as a tool for understanding the function of the receptor, it has drawbacks, including a short in vivo half-life and hypoadrenocorticism toxicity in rats and dogs, that prevented advancing it into clinical studies. Further research let to the discovery of JNJ 39758979, which, similar to JNJ 7777120, was a potent and selective H4R antagonist and showed anti-inflammatory and anti-pruritic activity preclinically. JNJ 39758979 advanced into human clinical studies and showed efficacy in reducing experimental pruritus and in patients with atopic dermatitis. However, development of this compound was terminated due to the occurrence of drug-induced agranulocytosis. This was overcome by developing another H4R antagonist with a different chemical structure, toreforant, that does not appear to have this side effect. Toreforant has been tested in clinical studies in patients with rheumatoid arthritis, asthma, or psoriasis. In conclusions there have been many H4R antagonists reported in the literature, but only a few have been studied in humans underscoring the difficulty in finding ligands with all of the properties necessary for testing in the clinic. Nevertheless, the clinical data to date suggests that H4R antagonists can be beneficial in treating atopic dermatitis and pruritus.
An Immunohistochemical Investigation of Renal Phospholipidosis and Toxicity in Rats
Immunohistochemical staining for the lysosome-associated membrane protein 2 (LAMP-2) has been proposed previously as an alternative to electron microscopy to identify hepatic phospholipidosis. This study used LAMP-2 immunohistochemistry (IHC) to diagnose phospholipidosis in rats exhibiting renal tubular injury. Rats were administered toreforant, a histamine H4 receptor antagonist by oral gavage at a dose of 3, 10, or 100 mg/kg/d for 6 months. Hematoxylin and eosin staining revealed renal tubular epithelial cell vacuolation, hypertrophy, degeneration, and luminal dilation in the 100 mg/kg/d group animals. Renal tubular injury was confirmed using kidney injury marker 1 (KIM-1) IHC. The involvement of phosopholipidosis in the renal injury was investigated by LAMP-2. Adipophilin IHC was included to differentiate phospholipidosis from lipidosis. Increased LAMP-2 staining was observed in the 100 mg/kg/d group animals when compared to vehicle group animals. Lysosome-associated membrane protein-2 staining was most prominent in the outer stripe of the outer medulla where KIM-1 staining was also most prominent. By contrast, adipophilin staining was not increased. Phospholipidosis was also confirmed by electron microscopy. These data support the use of LAMP-2 IHC as a diagnostic tool and suggest an association between phospholipidosis and the renal tubular injury caused by toreforant.
Toreforant, A Histamine H4 Receptor Antagonist, in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: Results of 2 Phase II Studies
Objective: To assess toreforant (selective histamine H4 receptor antagonist) in active rheumatoid arthritis (RA).
Methods: In a phase IIa, double-blind, placebo-controlled test, 86 patients were randomized (2:1) to once-daily toreforant 100 mg or placebo for 12 weeks. In phase IIb, double-blind, placebo-controlled, dose-range-finding evaluations, 272 patients were randomized (1:1:1:1) to once-daily placebo or toreforant 3/10/30 mg. Primary efficacy endpoints for both studies were Week 12 changes in 28-joint Disease Activity Score-C-reactive protein (DAS28-CRP).
Results: Phase IIa testing was terminated prematurely (patient fatality; secondary hemophagocytic lymphohistiocytosis). Posthoc analyses indicated toreforant 100 mg/day reduced RA signs/symptoms through Week 12. Phase IIb testing, however, showed no significant Week 12 improvement in DAS28-CRP with toreforant.
Conclusion: Toreforant was not effective in phase IIb testing.
Toreforant, an orally active histamine H4-receptor antagonist, in patients with active rheumatoid arthritis despite methotrexate: mechanism of action results from a phase 2, multicenter, randomized, double-blind, placebo-controlled synovial biopsy study
Objective/design: In a double-blind, placebo-controlled, multiple-dose study, we assessed the molecular mechanism of action of the selective histamine-4-receptor antagonist toreforant.
Patients/treatment: Patients with active rheumatoid arthritis (RA) despite methotrexate were randomized (3:1) to toreforant 30 mg/day (weeks 0-52) or placebo (weeks 0-12) followed by toreforant 30 mg/day (weeks 12-52).
Methods: Primary biomarker analyses comprised 39 different proteins/mRNA transcripts measured in synovial biopsy (n = 39) and/or time-matched serum (n = 15) samples collected at baseline and week 6. Clinical response was assessed using C-reactive protein-based 28-joint disease activity scores. Data were summarized using descriptive statistics.
Results: Among 21 randomized, treated patients (toreforant-16, placebo-5), 18 (toreforant-13, placebo-5) completed the 12-week double-blind period (none completed open-label treatment) prior to the early study termination. Biomarker profiling indicated potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-alpha, and interleukin-8 in synovium. Potential trends between biomarkers and clinical response were observed with synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3. Minimal synovial gene expression of interleukins-17A and 17F was detected.
Conclusions: While clear biomarker signals associated with toreforant pharmacology in RA patients were not identified, modest associations between biomarkers and clinical response were noted. Synovial expression of interleukins-17A/17F was minimal. Limited sample size warrants cautious interpretation.
Efficacy and Safety of Toreforant, a Selective Histamine H4 Receptor Antagonist, for the Treatment of Moderate-to-Severe Plaque Psoriasis: Results from a Phase 2 Multicenter, Randomized, Double-blind, Placebo-controlled Trial
Background: Toreforant is a selective histamine H4 receptor antagonist. H4 receptor activation may play a role in immune-mediated inflammation in psoriasis.
Objective: To evaluate Toreforant efficacy and safety in patients with moderate-to-severe psoriasis.
Methods: Biologic-na?ve patients were to be treated (30, 60, or 3 mg Toreforant or placebo) for 12 weeks and followed through week 16. In this adaptive-design study, assignments were guided by interim analyses. Primary and major secondary efficacy endpoints, evaluated using Bayesian analyses, were the proportions of patients achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI) from baseline and achieving Investigator's Global Assessment (IGA) of cleared (0) or minimal (1), respectively, at week 12.
Results: Per interim analyses results, patients were randomized to 30 (n = 30) or 60 mg (n = 26) Toreforant or placebo (n = 6). The estimated mean difference in the PASI 75 response rate at week 12 from the posterior distributions compared to placebo was 14.1% (95% credible interval [CI], -0.1% to 30.9%) and 8.9% (95% CI, -5.0% to 24.3%) with 30 and 60 mg Toreforant, respectively. The posterior probabilities of 30 and 60 mg Toreforant inducing a greater response rate than placebo were 97.4% and 90.3%, respectively; neither met the 97.5% predefined success criterion. Results for the IGA 0/1 endpoint were similar. Toreforant was generally safe and well tolerated. No deaths, serious or opportunistic infections, active tuberculosis, or malignancies were reported.
Conclusions: Toreforant efficacy at 30 and 60 mg was greater than placebo but did not meet predefined success criterion. J Drugs Dermatol. 2018;17(8):873-879.