HTL14242
(Synonyms: HTL0014242) 目录号 : GC63008
HTL14242 (HTL0014242) 是一种高级、口服活性强的 mGlu5 负变构调制器，其 pKi 和 pIC50 值分别为 9.3 和 9.2。HTL14242 可用于帕金森病的研究。
Cas No.:1644645-32-8
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
HTL14242 (HTL0014242) is an advanced and orally active mGlu5 NAM with a pKi and a pIC50 of 9.3 and 9.2, respectively[1]. HTL14242 can be used for the research of parkinson’s disease[2].
HTL14242 is stable in rat plasma, inactive at the hERG ion-channel, and has a clean profile in vitro assays of cytotoxicity in HepG2 cells, the TC50 is >90 μM[1].
HTL14242 (oral administration; 1, 3, or 10 mg/kg; sacrificed 1 h postdose) emonstrates an excellent, dose-dependent occupancy of mGlu5 receptors from an oral dose, with an estimated ED50 of 0.3 mg/kg[1]. HTL14242 (oral administration; 1 mg/ml) exhibits an oral PK Profile, the t1/2, AUCinf and F% are 6.5 hours, 3946 ng/h/mL and 80%, respectively in dog[1].
[1]. Kirstie A Bennett, et al. Structure-based Discovery and Development of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators. Adv Pharmacol. . 2020;88:35-58.
[2]. John A Christopher, et al. Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J Med Chem. . 2015 Aug 27;58(16):6653-64.
| Cas No. | 1644645-32-8 | SDF | |
| 别名 | HTL0014242 | ||
| 分子式 | C16H8ClFN4 | 分子量 | 310.71 |
| 溶解度 | DMSO : 12.5 mg/mL (40.23 mM; Need ultrasonic) | 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 | 3.2184 mL | 16.0922 mL | 32.1844 mL |
| 5 mM | 0.6437 mL | 3.2184 mL | 6.4369 mL |
| 10 mM | 0.3218 mL | 1.6092 mL | 3.2184 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。
Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)
J Med Chem 2015 Aug 27;58(16):6653-64.PMID:26225459DOI:10.1021/acs.jmedchem.5b00892.
Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 Å, respectively.
The use of conformationally thermostabilised GPCRs in drug discovery: application to fragment, structure and biophysical techniques
Curr Opin Pharmacol 2016 Oct;30:8-13.PMID:27400445DOI:10.1016/j.coph.2016.06.010.
Recent developments in receptor stabilisation have facilitated major advances in G protein-coupled receptor (GPCR) research, notably structural biology, over the past eight years. Here we review the application of fragment, structure and biophysical techniques using stabilised GPCRs (StaR proteins), and their impact in the drug discovery process. These techniques have, most recently, been utilised in the discovery of the non-alkyne mGlu5 negative allosteric modulator HTL14242, in addition to the dual orexin receptor antagonist HTL6641, with differentiated residence time kinetics.