ABX-1431

MGLL (mouse):27 nM|MGLL (human):14 nM

在体内，ABX-1431抑制啮齿动物脑内的MGLL活性（ED50=0.5-1.4 mg/kg），提高脑内2-AG浓度，并在大鼠甲醛疼痛模型中抑制疼痛行为。

ABX-1431是一种强效的人类MGLL抑制剂（平均IC50值为0.014 μM），对ABHD6具有超过100倍的选择性，对PLA2G7具有超过200倍的选择性。在对完整的人类PC3细胞进行处理时，经过30分钟的抑制剂孵育之后，ABX-1431对MGLL活性产生了浓度依赖性的抑制，其IC50值为0.0022 μM，约为体外观察到的效力的6倍。在细胞基础实验中，维持了对MGLL超过100倍的选择性，相比之下，ABHD6的IC50值为0.253 μM，PLA2G7的IC50值为494 μM。

Ethanol:10 mg/mL (19.71 mM);H2O:Insoluble;DMSO:55 mg/mL (108.4 mM)

Human prostate cancer PC3 cells were grown in F-12K medium supplemented with 10% fetal bovine serum at 37°C with 5% CO2 to ~80% confluency in 100 mm dishes. ABX-1431 was added to cells to give final concentration of 0.1–10 μM compound in serum free media. Cells were incubated with compound for 30 min at 37°C with 5% CO2. Cells were washed, harvested, and lysed by probe sonication. Cell lysates (2mg/mL) were treated with JW912 (1μM) and analyzed by SDS-PAGE and in-gel fluorescence scanning.

All animals were 6?8 weeks old at the time of study and weighed between 197-217 g. Animals (n = 3 per dosing route) were dosed with ABX-1431 at 1 mg/kg iv (in 70% polyethylene glycol (PEG) 400 in hydroxypropyl-?-cylcodextran (HPBCD) in saline) or 5 mg/kg po (in 70% PEG 400 in 0.5% carboxymethylcellulose (CMC, w/v) in saline). Animals were fasted overnight, and food withheld until 4 h post dose. Approximately 100 μL of blood were collected via a jugular vein catheter at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after intravenous and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration. All blood samples were collected into tubes containing 400 μL acetonitrile to immediately inactivate blood esterase activity and frozen at ?80 °C. Samples were thawed and centrifuged (14,000 rpm for 5 min at 4 °C) and the supernatant transferred for LCMS analysis.