GDC-0310
目录号 : GC64206
GDC-0310 是选择性的 Nav1.7 酰磺酰胺抑制剂，其对 hNav1.7 的 IC50 值为 0.6 nM。
Cas No.:1788063-52-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
GDC-0310 is a selective acyl-sulfonamide Nav1.7 inhibitor, with an IC50 of 0.6 nM for hNav1.7[1].
GDC-0310 exhibits an EC50 of 1.1 μM in vivo and a Ki of 1.8 nM for Nav1.7[1].
GDC-0310 shows substantially improved Nav selectivity and ADME properties[1].GDC-0310 exhibits t1/2 values of 5 h, 46 h and 4.4 h in rat (5 mg/kg, iv), dog (1 mg/kg, iv) and cynomolgus monkeys (2 mg/kg, iv), respectively[1].
[1]. Brian S Safina, et al. Discovery of Acyl-sulfonamide Na v 1.7 Inhibitors GDC-0276 and GDC-0310. J Med Chem. 2021 Mar 25;64(6):2953-2966.
[2]. Lei Xu, et al. Voltage-gated sodium channels: structures, functions, and molecular modeling. Drug Discov Today. 2019 Jul;24(7):1389-1397.
| Cas No. | 1788063-52-4 | SDF | Download SDF |
| 分子式 | C25H29Cl2FN2O4S | 分子量 | 543.48 |
| 溶解度 | 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 | 1.84 mL | 9.2 mL | 18.3999 mL |
| 5 mM | 0.368 mL | 1.84 mL | 3.68 mL |
| 10 mM | 0.184 mL | 0.92 mL | 1.84 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.
Cryo-EM reveals an unprecedented binding site for NaV1.7 inhibitors enabling rational design of potent hybrid inhibitors
Elife 2023 Mar 28;12:e84151.PMID:36975198DOI:10.7554/eLife.84151.
The voltage-gated sodium (NaV) channel NaV1.7 has been identified as a potential novel analgesic target due to its involvement in human pain syndromes. However, clinically available NaV channel blocking drugs are not selective among the nine NaV channel subtypes, NaV1.1-NaV1.9. Moreover, the two currently known classes of NaV1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. To this point understanding of the structure-activity relationships of the acylsulfonamide class of NaV1.7 inhibitors, exemplified by the clinical development candidate GDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor bound to voltage-sensing domain 4 (VSD4). To advance inhibitor design targeting the NaV1.7 channel, we pursued high-resolution ligand-bound NaV1.7-VSD4 structures using cryogenic electron microscopy (cryo-EM). Here, we report that GDC-0310 engages the NaV1.7-VSD4 through an unexpected binding mode orthogonal to the arylsulfonamide inhibitor class binding pose, which identifies a previously unknown ligand binding site in NaV channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl- and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, our study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design This work also underscores an important role of the membrane bilayer in the optimization of selective NaV channel modulators targeting VSD4.