JH-II-127一种口服有效的，具有高效力、选择性和脑渗透性的LRRK2抑制剂，其对野生型的LRRK2和LRRK2-G2019S以及突变型的LRRK2-A2016T的IC50值分别为6、2 和 48 nM。JH-II-127 能够抑制小鼠包括大脑在内的所有组织中的Ser935磷酸化。JH-II-127 可用于帕金森综合征的研究。
| 生物活性 | JH-II-127 is an orally active, highly potent, selective and brain-permeableLRRK2inhibitor, withIC50s of 6, 2 and 48 nM for wild-typeLRRK2andLRRK2-G2019Sand mutantLRRK2-A2016T. JH-II-127 inhibitsSer935phosphorylation in all tissues of mice, including the brain. JH-II-127 can be used in the study of parkinson's syndrome[1]. |
体外研究
(In Vitro) | JH-II-127 (0.03, 0.1, 0.3, 1, 3 μM; 90 min) inhibits LRRK2 in HEK293 cells[1].
JH-II-127 (0.3, 1, 3 μM; 90 min) inhibits endogenously expressed LRRK2 in mouse Swiss 3T3 cells[1].
Western Blot Analysis[1] | Cell Line: | HEK293 cells (expressing GFP-LRRK2, GFP-LRRK2[G2019S], GFP-LRRK2[G2019S + A2016T], and GFP-LRRK2[A2016T], respectively) | | Concentration: | 0.03, 0.1, 0.3, 1, 3 μM | | Incubation Time: | 90 min | | Result: | Induced a dose-dependent inhibition of Ser910 and Ser935 phosphorylation in both wild-type LRRK2 and LRRK2[G2019S] stably transfected into HEK293 cells.
Inhibited phosphorylation of Ser910 and Ser935 at approximately 0.3 μM for wild-type LRRK2 and LRRK2[G2019S].
Induced dephosphorylation of Ser910 and Ser935 at a concentration of 0.3-1 μM in the drug-resistant LRRK2[A2016T + G2019S] and LRRK2[A2016T] mutants. |
Western Blot Analysis[1] | Cell Line: | Mouse Swiss 3T3 cells | | Concentration: | 0.03, 0.1, 0.3, 1, 3 μM | | Incubation Time: | 90 min | | Result: | Induced similar dose-dependent Ser935 dephosphorylation of endogenous LRRK2. |
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体内研究
(In Vivo) | JH-II-127 (100 mg/kg; i.p.; single) results in near complete dephosphorylation of Ser935 of LRRK2 in all tissues including brain[1].
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Pharmacokinetic Parameters of JH-II-127 in Wild type male C57BL/6 mice[1]. | matrix | route | Tmax(h) | C0/Cmax(ng/mL) | AUCLast(hong/mL) | AUGINF(hong/mL) | T1/2(h) | CL (mL/min/kg) | Vss(L/kg) | | plasma | IV (2 mg/kg) | - | 1604.47 | 532.67 | 535.57 | 0.66 | 62.24 | 1.73 | | plasma | PO (10 mg/kg) | 1 | 802.72 | 3094.58 | 3867.07 | - | - | - | | brain | IV (2 mg/kg) | - | 1343.6 | 239.31 | 246.47 | 0.23 | 135.24 | 1.7 | | brain | PO (10 mg/kg) | 1 | 247.35 | 688.21 | 762.38 | - | - | - | |
| Animal Model: | Wild type male C57BL/6 mice[1]. | | Dosage: | 2 mg/kg (for i.v.); 10 mg/kg (for p.o.); 10, 30, 100 mg/kg (for i.p.) | | Administration: | Intravenous and intraperitoneal injection; oral administration; single. | | Result: | Led to near complete dephosphorylation of Ser935 of LRRK2 in all tissues including brain when at 100 mg/kg of i.p. and near complete inhibition in all tissues at 30 mg/kg but only partial inhibition in brain at the 10 mg/kg dose.
Demonstrated good oral bioavailability. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : 110 mg/mL(263.88 mM;Need ultrasonic) 配制储备液 | 1 mM | 2.3989 mL | 11.9944 mL | 23.9889 mL | | 5 mM | 0.4798 mL | 2.3989 mL | 4.7978 mL | | 10 mM | 0.2399 mL | 1.1994 mL | 2.3989 mL |
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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半岛bd体育手机客户端
失效。
储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液，再依次添加助溶剂： ——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用；
以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂： 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.75 mg/mL (6.60 mM); Clear solution
此方案可获得 ≥ 2.75 mg/mL (6.60 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 27.5 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。 2. 请依序添加每种溶剂： 10% DMSO 90%corn oil Solubility: ≥ 2.75 mg/mL (6.60 mM); Clear solution
此方案可获得 ≥ 2.75 mg/mL (6.60 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。 以 1 mL 工作液为例，取 100 μL 27.5 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。 *以上所有助溶剂都可在本网站选购。
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