对于重组同源三聚体 hP2X1、hP2X2、hP2X4、rP2X5 和 hP2X7 通道，IC50 值大于 10,000 nM，表明 gefapixant 对任何含有非 P2X3 亚基的受体没有抑制作用 [1]。

在膝骨关节炎大鼠模型中，关节内单碘乙酸注射后 14 天内，吉法匹克特（7 天 bid，口服）完全逆转了明显的痛觉过敏，并在两个较高剂量下减少了负重偏侧性 [2]。

芳基嘧啶二胺，Gefapixant/AF-219 (Ford et al., 2013；Smith等人，2013)是一种口服活性的小分子（Mol Wt. ~ 350道尔顿）拮抗剂，用于人类含p2x3受体。据报道，af219对重组hP2X3三聚体的抑制效价（IC50）为~ 30 nM，对hP2X2/3异三聚体受体的抑制效价（IC50）为100-250 nM，与重组大鼠受体的抑制效价非常相似，并且对含有非p2x3亚基的受体没有抑制作用（在重组hP2X1， hP2X2, hP2X4， rP2X5和hP2X7通道的IC50值比10000 nM要高）。来自P2X3选择性嘧啶二胺类其他相关化学成员的报告表明，抑制机制是非竞争性的（变构），并且在P2X3受体效价估计的物种独立性方面存在混合：AF-353 （Gever等人，2010）在人类和大鼠重组P2X3三聚体之间显示出显著的效价一致性（IC50值分别为8.7和8.9 nM），而更有效的类似物AF-792(也称为RO-51；在一份报告中（Serrano等人，2012）显示，最初作为AF-353的潜在前药而开发的P2X3对人类和大鼠的P2X3受体的效力较弱，但在另一份报告中（Jahangir等人，2009）显示其与物种无关。值得注意的是，对P2X3和P2X3 /3通道的选择性是几种化学类抑制剂的共同主张（参见Gum等人，2012：例如AF-219类似物，核苷酸如TNP-ATP，苯三羧酸如a -317491），尽管在大多数研究中报告的值不是亲和力测定，而是IC50估计。在这种情况下，真正的选择性不能绝对推断，特别是对于竞争性拮抗剂（如TNP-ATP和a -317491），因为IC50是一个参数，它会随着使用的激动剂浓度而变化，并取决于激动剂在不同三聚体上的效力。[1]

Absorption, Distribution and Excretion
The absolute bioavailability of gefapixant has not been evaluated but is estimated to be ≥78%. At the recommended dose of 45 mg twice daily, steady-state is achieved within 2 days and the steady-state mean plasma AUC and Cmax are 4,144 ng∙hr/mL and 531 ng/mL, respectively. The time to peak plasma concentration (Tmax) following oral administration ranges from one to four hours. The co-administration of gefapixant with a high-fat, high-calorie meal had no effect on its AUC or Cmax.
Gefapixant is primarily eliminated via renal excretion. Following a single oral radiolabeled dose in a healthy male subject, approximately 76.4% of the administered radioactivity was recovered in the urine and 22.6% was recovered in the feces. Unchanged parent drug accounted for 64% of the recovered dose in the feces and accounted for 20% of the recovered dose in the urine.
Based on population pharmacokinetic analyses, the estimated steady-state apparent volume of distribution is 133.8 L (Vc 101 L and Vp 32.8 L) following oral twice-daily administration of gefapixant 45 mg.
Population pharmacokinetic analyses integrating data from Phase 1, 2, and 3 data showed a geometric mean apparent clearance (Cl/F) of 10.8 L/h. In clinical pharmacology studies, the observed clearance was 14.8 L/h and renal clearance was approximately 8.7 L/h.

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Metabolism / Metabolites
Gefapixant is relatively minimally metabolized. Following oral administration, only 14% of the administered dose was recovered as metabolites in the urine and feces. Unchanged parent drug is the major (87%) drug-related component in plasma, with circulating metabolites accounting for <10% each. The primary biotransformation pathways observed in gefapixant ADME studies included hydroxylation, O-demethylation, dehydrogenation, oxidation, and direct glucuronidation. Secondary biotransformation pathways included glucuronidation of O-demethylated metabolite as well as the formation of a metabolite that was O-demethylated and hydrogenated. The three most abundant circulating metabolites were: M1 (a glucuronide of O-demethylated gefapixant), M5 (a directly glucuronidated parent) and M13 (a hydroxylated metabolite.), which accounted for 1.0%, 6.3%, and 5.8%, respectively, of the total drug-related components in plasma.

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Biological Half-Life
The terminal half-life of gefapixant is 6-10 hours.

Protein Binding
Gefapixant exhibits relatively low protein binding (55%) _in vitro_, and thus drug-drug interactions resulting from protein displacement are not expected.

[1]. Anthony P. Ford, et al. The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders. Front Cell Neurosci. 2013; 7: 267.
[2]. Ford AP, In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization. Purinergic Signal. 2012 Feb;8(Suppl 1):3-26.
[3]. Martin Nguyen A, et al. Validation of a visual analog scale for assessing cough severity in patients with chronic cough. Ther Adv Respir Dis. 2021 Jan-Dec;15:17534666211049743

It has been estimated that 5-10% of adults globally suffer from chronic cough, which is defined as a cough lasting longer than eight weeks. A subset of these patients remain symptomatic despite thorough investigation and treatment, termed refractory chronic cough (RCC) if they have a cough that does not respond to conventional treatment or unexplained chronic cough (UCC) when no diagnosable cause for the cough can be determined. Existing treatments for chronic cough have been associated with considerable side effects, in particular opioids such as [codeine] or [dextromethorphan]. Gefapixant is a novel antagonist of the P2X3 receptor that works to reduce the cough reflex in patients with chronic cough. It received approval in both Japan and Switzerland in 2022 for the treatment of adult patients with RCC and UCC, and received subsequent approval in the EU in September 2023 for the same indications. It is the first therapy to be approved for the treatment of RCC or UCC in the EU.

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Drug Indication
Gefapixant is indicated in adult patients for the treatment of refractory or unexplained chronic cough.
Lyfnua is indicated in adults for the treatment of refractory or unexplained chronic cough.

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Mechanism of Action
Gefapixant is a selective antagonist of P2X3 receptors, with some activity against the P2X2/3 receptor subtype. P2X3 receptors are ATP-gated ion channels found on sensory C fibers of the vagus nerve in the airways. Under inflammatory conditions, ATP is released from airway mucosal cells where it can subsequently bind to P2X3 receptors on C fibers. The activation of vagal C fibers is perceived as an urge to cough and initiates a cough reflex. Gefapixant inhibits the binding of ATP to P2X3 receptors, thereby reducing excessive C fiber activation by extracellular ATP and dampening the subsequent cough reflex.

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Pharmacodynamics
Gefapixant exerts its therapeutic effects via suppressing the cough reflex initiated by sensory C fibers of the vagus nerve. In clinical studies, patients experienced a significant reduction in 24-hour cough frequency compared to placebo - this reduction was apparent by Week 4 and persisted throughout the remainder of the primary efficacy period. As renal excretion is the primary route of elimination for gefapixant, patients with severe renal impairment (eGFR < 30 mL/min/1.73m²) may require dose adjustment to maintain appropriate systemic exposures.

C14H19N5O4S

353.39676117897

353.115

C, 47.58; H, 5.42; N, 19.82; O, 18.11; S, 9.07

1015787-98-0

Gefapixant citrate;2310299-91-1

24764487

Typically exists as White to off-white solid at room temperature

1.4±0.1 g/cm3

606.3±65.0 °C at 760 mmHg

320.5±34.3 °C

0.0±1.7 mmHg at 25°C

1.615

0.73

165

3

9

5

24

512

0

S(C1=CC(=C(C=C1OC)C(C)C)OC1=CN=C(N)N=C1N)(N)(=O)=O

HLWURFKMDLAKOD-UHFFFAOYSA-N

InChI=1S/C14H19N5O4S/c1-7(2)8-4-10(22-3)12(24(17,20)21)5-9(8)23-11-6-18-14(16)19-13(11)15/h4-7H,1-3H3,(H2,17,20,21)(H4,15,16,18,19)

5-(2,4-diaminopyrimidin-5-yl)oxy-2-methoxy-4-propan-2-ylbenzenesulfonamide

AF-219; Gefapixant [USAN]; Benzenesulfonamide, 5-[(2,4-diamino-5-pyrimidinyl)oxy]-2-methoxy-4-(1-methylethyl)-; RO4926219; RG-1646; Ro-4926219;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ~5 mg/mL (~14.15 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.07 mM) (饱和度未知) in 10% DMSO + 90% PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。

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配方 2 中的溶解度: ≥ 0.5 mg/mL (1.41 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 5.0 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 0.5 mg/mL (1.41 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，将 100 μL 5.0 mg/mL 澄清 DMSO 储备液加入 900 μL 20% SBE-β-CD 生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 4 中的溶解度: ≥ 0.5 mg/mL (1.41 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 5.0 mg/mL澄清DMSO储备液加入900 μL玉米油中，混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。