BLU-5937
目录号 : GC60090
BLU-5937 是一种有效的，选择性的，口服活性的 P2X3 同型三聚体受体拮抗剂，对人 P2X3，大鼠 P2X3 和豚鼠 P2X3 受体的 IC50 分别为 25 nM，92 nM 和 126 nM。BLU-5937 对人，大鼠和豚鼠 P2X2/3 异三聚体受体的活性较低。BLU-5937 具有很强的镇咳作用。
Cas No.:2417288-67-4
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: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
BLU-5937 is a potent, selective and orally active P2X3 homotrimeric receptor antagonist with IC50s of 25?nM, 92?nM and 126?nM for human P2X3, rat P2X3 and guinea pig P2X3 receptors, respectively. BLU-5937 is less active against human, rat and guinea pig P2X2/3 heterotrimeric receptors. BLU-5937 has strong anti-tussive effect[1].
BLU-5937 (500?nM) is able to block αβ-meATP-induced sensitization and firing activity of isolated primary nociceptors in rat dorsal root ganglions (DRGs), through P2X3 homotrimeric receptor antagonism. The sensitizing effect of αβ-meATP and the inhibition of BLU-5937 are reversible after washout[1].
BLU-5937 (0.3-0mg/kg, oral administration; male Dunkin Hartley guinea pigs) treatment significantly reduces the histamine-induced enhancement in the number of citric acid-induced coughs in a dose-dependent fashion in a guinea pig cough model[1].BLU-5937 (3 and 30mg/kg, oral) is also shown to reduce significantly and dose-dependently the ATP-induced enhancement of citric acid-induced coughs in the guinea pig[1]. Animal Model: Male Dunkin Hartley guinea pigs[1]
[1]. Garceau D, et al. BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulm Pharmacol Ther. 2019 Jun;56:56-62.
| Cas No. | 2417288-67-4 | SDF | |
| Canonical SMILES | O=C(OC)N1C[C@@H](CCC1)CC2=C(N=C3C=C(C=CN32)C)C4=C(C=C(C=C4F)C(NC)=O)F | ||
| 分子式 | C24H26F2N4O3 | 分子量 | 456.49 |
| 溶解度 | 储存条件 | -20°C, protect from light | |
| 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 | 2.1906 mL | 10.9531 mL | 21.9063 mL |
| 5 mM | 0.4381 mL | 2.1906 mL | 4.3813 mL |
| 10 mM | 0.2191 mL | 1.0953 mL | 2.1906 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。
BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration
Pulm Pharmacol Ther 2019 Jun;56:56-62.PMID:30902655DOI:10.1016/j.pupt.2019.03.007.
BLU-5937 is a small molecule that was shown to be a potent, selective and non-competitive P2X3 homotrimeric receptor antagonist. P2X3 receptors are ATP ion-gated channels located on primary afferent neurons. ATP released from damaged or inflamed tissues in the airways acts on P2X3 receptors of primary afferent neurons, triggering depolarization and action potentials that are transmitted centrally and interpreted as urge to cough. There are strong preclinical and clinical evidence supporting the role of P2X3 receptors in hypersensitization of the cough reflex, leading to chronic cough. By inhibiting P2X3 receptors on the primary sensory neurons, BLU-5937 would inhibit the hypersensitization of the cough reflex and, hence, the exaggerated cough experienced in chronic cough patients. BLU-5937 is being developed for the treatment of unexplained, refractory chronic cough. The high potency and selectivity of BLU-5937 for P2X3 homotrimeric receptors was demonstrated in vitro by inhibiting αβ-meATP-evoked P2X3 or P2X2/3 receptor activity in cloned human hP2X3 and hP2X2/3 channels expressed in mammalian cells. The IC50 of BLU-5937 for hP2X3 homotrimeric and hP2X2/3 heterotrimeric receptors was established at 25 nM and >24 μM, respectively. Furthermore, BLU-5937 (500 nM) was able to block αβ-meATP-induced sensitization and firing activity of isolated primary nociceptors in rat dorsal root ganglions (DRGs), through P2X3 homotrimeric receptor antagonism. In a guinea pig cough model, BLU-5937 (0.3, 3 and 30 mg/kg, oral) significantly reduced, in a dose-dependent fashion, the histamine-induced enhancement in the number of citric acid-induced coughs. BLU-5937 (3 and 30 mg/kg, oral) was also shown to reduce significantly and dose-dependently the ATP-induced enhancement of citric acid-induced coughs in the guinea pig. These anti-tussive effects were obtained at a plasma concentration known to block P2X3 homotrimeric receptors, but at concentration 50-fold lower than that required to block P2X2/3 heterotrimeric receptors. These results indicate that the anti-tussive effect of BLU-5937 is primarily mediated through the inhibition of P2X3 homotrimeric receptors. In a rat behavioral taste model, BLU-5937 (10-20 mg/kg, IP) did not alter taste perception as compared to control animals. In the same experiment, N-00588 (10-20 mg/kg, IP), a weakly selective antagonist for P2X3 versus P2X2/3 receptors, had a significant inhibitory effect on taste perception. Pharmacokinetic analysis of drug plasma concentrations showed that BLU-5937 did not affect taste function at concentrations up to 30 times the IC50 for P2X3. These results suggest that N-00588 achieved systemic concentration that blocked P2X3 and P2X2/3 receptors expressed on gustatory nerve ending innervating taste buds. The lack of effect of BLU-5937, even at high doses, on taste perception may be attributed to its higher selectivity for the P2X3 versus P2X2/3 receptors on the taste buds. The safety, tolerability and pharmacokinetic profile of BLU-5937 was assessed in a battery of preclinical studies and have revealed that BLU-5937 exhibits excellent drug-like characteristics, including good oral bioavailability, low predicted clearance in human, no blood-brain barrier permeability and high safety margin versus human predicted efficacious exposure. BLU-5937 is currently in clinical phase I development stage. In conclusion, BLU-5937 was selected as a drug candidate for the treatment of chronic cough due to its high potency and selectivity for P2X3 homotrimeric receptors, strong anti-tussive effects, excellent tolerability and predicted pharmacokinetic properties in humans.
Update on novel purinergic P2X3 and P2X2/3 receptor antagonists and their potential therapeutic applications
Expert Opin Ther Pat 2019 Dec;29(12):943-963.PMID:31726893DOI:10.1080/13543776.2019.1693542.
Introduction: Purinergic P2X3-P2X2/3 receptors are placed in nociceptive neurons' strategic location and show unique desensitization properties; hence, they represent an attractive target for many pain-related diseases. Therefore, a broad interest from academic and pharmaceutical scientists has focused on the search for P2X3 and P2X2/3 receptor ligands and has led to the discovery of numerous new selective antagonists. Some of them have been studied in clinical trials for the treatment of pathological conditions such as bladder disorders, gastrointestinal and chronic obstructive pulmonary diseases.Areas covered: This review provides a summary of the patents concerning the discovery of P2X3 and/or P2X2/3 receptor antagonists published between 2015 and 2019 and their potential clinical use. Thus, the structures and biological data of the most representative molecules are reported.Expert opinion: The 2016 publication of the crystallographic structure of the human P2X3 receptor subtype gave an improvement of published patents in 2017. Hence, a great number of small molecules with dual antagonist activity on P2X3-P2X2/3 receptors, a favorable pharmacokinetic profile, and reasonable oral bioavailability was discovered. The most promising compounds are the phenoxy-diaminopyrimidines including gefapixant (AF-219), and the imidazo-pyridines like BLU-5937, which are in phase III and phase II clinical trials, respectively, for refractory chronic cough.
Managed care considerations for the treatment of chronic cough
Am J Manag Care 2022 Sep;28(9 Suppl):S166-S174.PMID:36198075DOI:10.37765/ajmc.2022.89245.
Chronic cough (CC), defined as a daily cough lasting longer than 8 weeks in adults, is a common condition in the United States. CC is a diagnosis of exclusion associated with a substantial economic burden related to increased healthcare and medication utilization, decreased work productivity, a greater incidence of cough-related comorbidities, and reduced quality of life. CC treatment guidelines recommend stepwise treatment with specific nonpharmacologic therapies and pharmacologic agents. However, many patients may still have incomplete or no symptom relief, encounter response attenuation over time, or experience intolerable adverse effects. New targeted therapies for refractory CC are currently under development, including the purinergic 2X3 receptor antagonists gefapixant, BLU-5937, and sivopixant (S-600918) and the neurokinin-1 receptor antagonist orvepitant. These targeted agents may have improved efficacy and safety profiles, helping fill unmet treatment needs. If approved, managed care organizations must develop formulary placement and utilization management criteria based on clinical guideline recommendations, expert opinion, and cost-effectiveness analyses to support the clinically appropriate use of these targeted therapies for best patient outcomes.