GDC-2394 是一种口服有效、选择性的NLRP3抑制剂,同时也抑制IL-1β,IC50为 0.4 μM (human IL-1β) 和 0.1 μM (mouse IL-1β)。GDC-2394 抑制 NLRP3 诱导的caspase-1活性,但不抑制 NLRC4 依赖的炎症小体激活。
生物活性 | GDC-2394 is an orally active and selectiveNLRP3inhibitor, and also inhibitsIL-1βwithIC50s of 0.4 μM (human IL-1β) and 0.1 μM (mouse IL-1β). GDC-2394 inhibits NLRP3-inducedcaspase-1activity without inhibiting NLRC4-dependent inflammasome activation[1][2]. |
体外研究 (In Vitro) | GDC-2394 (20 μM; 30 min) inhibits NLRP3-induced apoptosis associated speck-like protein containing CARD (ASC) speck formation in THP-1 cells[1]. GDC-2394 (1 nM-10 μM; 7 d) inhibits human macrophage IL-1β and IL-18 production after activation of the NLRP3 inflammasome[1]. GDC-2394 (0-20 μM; 30 min) inhibits NLRP3-dependent caspase-1 activation (IC50=51 nM) in THP-1 cells, also inhibits NLRP3-dependent IL-1β release (IC50=63 nM) and NLRC4-dependent IL-1β release (IC50>20 μM) in mouse bone marrow-derived macrophages (mBMDMs)[1].
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体内研究 (In Vivo) | GDC-2394 (compound 20) (1 mg/kg, 10 mg/kg; p.o.; single dose) inhibits production of IL-1β in an acute mouse peritonitis model[1]. GDC-2394 (25 mg/kg; once daily for 7 d) reduces paw swelling and pain in a functional rat model of gouty arthritis[1].
Preclinical PK of GDC-2394[1].
Species | Mouse | Rat | Dog | Cyno | CLp(mL/min/kg) | 10.1 | 1.3 | 11.7 | 4.1 | Vss(L/kg) | 0.72 | 0.29 | 0.67 | 0.18 | T1/2(h) | 1.2 | 4.4 | 0.99 | 0.89 | %F (1 mg/kg) | 80 | 33 | 78 | 53 |
Animal Model: | Acute mouse peritonitis model[1] | Dosage: | 1 mg/kg and 10 mg/kg | Administration: | Oral gavage; 2 h later treated with 1.25 μg LPS (i.p.) followed by 1 mg monosodium urate crystals (i.p.) a further 2 h later. | Result: | Resulted in a dose-dependent decrease in peritoneal IL-1β concentrations after MSU treatment, and decreased the level of IL-1β by 66.8 and 81.3% at 1 and 10 mg/kg compared with the control. |
Animal Model: | Functional rat model of gouty arthritis[1] | Dosage: | 25 mg/kg | Administration: | Interventional injection; once daily for 7 days | Result: | Significantly inhibited knee swelling after 48 h. |
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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 | In solvent | -80°C | 6 months | | -20°C | 1 month |
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溶解性数据 | In Vitro: DMSO : 125 mg/mL(289.68 mM;Need ultrasonic) 配制储备液 1 mM | 2.3174 mL | 11.5872 mL | 23.1744 mL | 5 mM | 0.4635 mL | 2.3174 mL | 4.6349 mL | 10 mM | 0.2317 mL | 1.1587 mL | 2.3174 mL |
*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℃, 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: ≥ 2.08 mg/mL (4.82 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (4.82 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 20.8 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% (20%SBE-β-CDin saline) Solubility: ≥ 2.08 mg/mL (4.82 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (4.82 mM,饱和度未知) 的澄清溶液。 以 1 mL 工作液为例,取 100 μL 20.8 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中,混合均匀。 3. 请依序添加每种溶剂: 10% DMSO 90%corn oil Solubility: ≥ 2.08 mg/mL (4.82 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (4.82 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 20.8 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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