GDC-0276
目录号 : GC39559
GDC-0276 是一种有效的、选择性的、可逆的口服活性 NaV1.7 抑制剂，其 IC50 值为 0.4 nM。GDC-0276 耐受性良好，显现良好的药代动力学特征。GDC-0276 有潜力用于治疗疼痛以及解决现有止痛药物缺陷，如成瘾和脱靶副作用的相关研究。
Cas No.:1494581-70-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
GDC-0276 is a potent, selective, reversible and orally active NaV1.7 inhibitor with an IC50 value of 0.4 nM. GDC-0276 is well tolerated and exhibits a good pharmacokinetic profile. GDC-0276 has the potential for the treatment of pain and to address shortcomings of existing pain medications, such as addiction and off-target side effects[1].
[1]. Rothenberg ME, et al. Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel NaV1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study i [2]. Steven J. McKerrall, et al. Nav1.7 inhibitors for the treatment of chronic pain. Bioorganic & Medicinal Chemistry Letters (2018) [3]. Takahashi RH,et al.Unequal Absorption of Radiolabeled and Nonradiolabeled Drug from the Oral Dose Leads to Incorrect Estimates of Drug Absorption and Circulating Metabolites in a Mass Balance Study.Drug Metab Lett. 2019;13(1):37-44.
| Cas No. | 1494581-70-2 | SDF | |
| Canonical SMILES | O=C(NS(=O)(N1CCC1)=O)C2=CC(C3CC3)=C(OCC4(C5)CC6CC5CC(C6)C4)C=C2F | ||
| 分子式 | C24H31FN2O4S | 分子量 | 462.58 |
| 溶解度 | DMSO: 125 mg/mL (270.22 mM) | 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。 |
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| 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 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1618 mL | 10.8089 mL | 21.6179 mL |
| 5 mM | 0.4324 mL | 2.1618 mL | 4.3236 mL |
| 10 mM | 0.2162 mL | 1.0809 mL | 2.1618 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。
Discovery of Acyl-sulfonamide Nav1.7 Inhibitors GDC-0276 and GDC-0310
J Med Chem 2021 Mar 25;64(6):2953-2966.PMID:33682420DOI:10.1021/acs.jmedchem.1c00049.
Nav1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 (1) and GDC-0310 (2), selective Nav1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3. This resulted in the discovery of GDC-0276 (1), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Nav1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Nav selectivity and pharmacokinetic profile over 1.
Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel NaV1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers
Clin Drug Investig 2019 Sep;39(9):873-887.PMID:31172446DOI:10.1007/s40261-019-00807-3.
Background and objective: Current pain therapies often do not provide adequate pain relief and have dose-limiting adverse effects. Genetic evidence indicates that NaV1.7 sodium channels are required for pain transduction and therefore represent an important therapeutic target. GDC-0276 is a novel NaV1.7 inhibitor developed for the treatment of pain. This first-in-human trial evaluated the safety, tolerability, and pharmacokinetics of orally administered GDC-0276 in healthy subjects. Methods: This phase I, randomized, double-blind, placebo-controlled study assessed GDC-0276 as powder-in-capsule (PIC) or cyclodextrin solution (CD) single doses (SDs) of 2-270 mg (seven cohorts) and 45-540 mg (five cohorts), respectively. Multiple (MD) PIC doses were administered as total daily doses of 15-540 mg divided into two or three doses/day, up to 10 or 14 days. Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, electrocardiograms, and laboratory tests for up to 15 days after the last day of dosing. GDC-0276 plasma pharmacokinetics were also determined. Results: Three stages included 183 randomized subjects. GDC-0276 plasma exposure increased with dose level for all stages. Exposure was higher in the SD-CD cohorts compared with the equivalent SD-PIC dose levels. SDs were adequately tolerated up to 270 mg (SD-PIC) and 360 mg (SD-CD). Hypotension limited tolerability in the 540-mg SD-CD cohort. Multiple PIC doses were tolerated up to 270 mg twice daily, however liver transaminase elevations were frequently observed. No deaths or serious AEs occurred. Conclusion: GDC-0276 exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for pain.
Isothermal Crystallization Monitoring and Time-Temperature-Transformation of Amorphous GDC-0276: Differential Scanning Calorimetric and Rheological Measurements
Mol Pharm 2021 Jan 4;18(1):158-173.PMID:33259220DOI:10.1021/acs.molpharmaceut.0c00776.
Cold crystallization of amorphous pharmaceuticals is an important aspect in the search to stabilize amorphous or glassy compounds used as amorphous pharmaceutical ingredients (APIs). In the present work, we report results for the isothermal crystallization of the compound GDC-0276 based on differential scanning calorimetric and rheometric measurements. The kinetics of isothermal crystallization from the induction time to the completion of crystallization can be described by the classic Johnson-Mehl-Avrami (JMA) equation. The time-temperature-transformation (TTT) diagrams were constructed for two time points-that of induction and that of completion of crystallization. The results show that the rheological measurement for GDC-0276 has a better overall sensitivity in detection of the early stage nucleation and, consequently, detects the onset of crystallization sooner than does the differential scanning calorimetry. Rheological measurements were also used to obtain the temperature dependence of the viscosity of GDC-0276 and the relevant parameters were used in a modified form of the JMA model to describe the temperature dependence of the crystal induction and completion times, that is, the TTT diagram for the material. In the modification, we assumed that the kinetics followed the viscosity to the 0.75 power as suggested by the recent work of Huang et al. (Huang, C., et al., J. Chem. Phys.2018,149, 054503). The relationship and the possible impact on crystallization kinetics of the break-down of the Stokes-Einstein relation in glass-forming liquids are discussed. From the crystallization kinetics modeling, the solid-liquid interfacial surface tension σSL was obtained for GDC-0276 and was compared with that obtained from the melting point depression measurements of the material confined in nanoporous glasses. The differences between the values from the two methods are discussed.
Correction to: Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel NaV1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers
Clin Drug Investig 2019 Sep;39(9):889-890.PMID:31338799DOI:10.1007/s40261-019-00832-2.
The original version of this article unfortunately contained a mistake. A few entries were incorrect in Table 2.
Unequal Absorption of Radiolabeled and Nonradiolabeled Drug from the Oral Dose Leads to Incorrect Estimates of Drug Absorption and Circulating Metabolites in a Mass Balance Study
Drug Metab Lett 2019;13(1):37-44.PMID:30499424DOI:10.2174/1872312813666181129162237.
Background: Mass balance studies conducted using radiolabeled material (14C or 3H) definitively characterize the Absorption, Metabolism, and Excretion (AME) of a drug. A critical aspect of these studies is that the radiotracer maintains its proportion to total drug from its administration to its complete elimination from the body. In the study of GDC-0276 in beagle dogs, we observed that the 14C radiotracer proportion (specific activity) varied through the study. Method: High resolution-accurate mass spectrometric measurements of 12C and 14C isotopes of GDC- 0276 and its metabolites in plasma and excreta samples were used to determine the apparent specific activities, which were higher than the specific activity of the dosing formulation. Drug concentrations were adjusted to the observed specific activities to correct the readouts for GDC-0276 AME and PK. Results: The enrichment of 14C, which resulted in higher specific activities, was consistent with faster and more extensive absorption of the radiotracer from the dosing formulation. This resulted in overestimating the dose absorbed, the extent of elimination in urine and bile, and the exposures to circulating metabolites. These biases were corrected by the specific activities determined for study samples by mass spectrometry. Conclusion: Assuming that the radiotracer was proportional to total drug throughout a radiolabeled study was not valid in a 14C study in beagle dogs. This presumably resulted from unequal absorption of the radiotracer and nonradiolabeled test articles from the oral dose due to inequivalent solid forms. We were able to provide a more accurate description of the AME of GDC-0276 in dogs by characterizing the differential absorption of the radiotracer.