Varespladib (LY315920) (Synonyms: Varespladib)

Chromogenic assay

Varespladib was evaluated in the assay containing 0.96 mM racemic 1,2-bis(thioheptanoyl)-1,2-dideoxyphosphatidylcholine, 0.27 mM Triton X-100, and 0.12 mM 5,5’-dithiobis[2-nitrobenzoic acid] (DTNB). Concentration-response curves were generated with 16 nM recombinant human sPLA2 for 30 mins at 40 °C in a microtiter plate format. IC50 values were determined as well as mole fraction for 50% inhibition (Xi50). Mole fraction represented a dimensionless number derived by dividing the IC50 value by the concentration of lipid in the assay mixture. IC50 values were determined in triplicate.

Cell lines

BAL cells

Preparation method

The solubility of this compound in DMSO is > 8.175 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months.

Reacting condition

0.1 ~ 3 μM

Applications

In BAL cells stimulated with human sPLA2, Varespladib (0.1 ~ 3 μM) inhibited the formation of thromboxane in a concentration-dependent manner, with an IC50 value of approximately 8 × 10-7 M. In control experiments, Varespladib (3 μM) showed no effect on formyl-methionyl-leucyl-phenylalanine (a chemotactic peptide)-induced thromboxane release. Similarly, arachidonic acid-induced generation of thromboxane A2 was not inhibited by prior exposure to Varespladib.

Animal models

Transgenic mice expressing human sPLA2 protein

Dosage form

0.3 ~ 3 mg/kg; i.v. or p.o.

Applications

In transgenic mice expressing human sPLA2 protein, Varespladib (0.3 ~ 3 mg/kg, i.v.) inhibited serum sPLA2 activity. However, the inhibition effect of Varespladib gradually decreased over the 4-hr observation period. Oral administration of Varespladib to transgenic mice leaded to similar dose-dependent inhibition on serum sPLA2 activity.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Snyder DW, Bach NJ, Dillard RD, Draheim SE, Carlson DG, Fox N, Roehm NW, Armstrong CT, Chang CH, Hartley LW, Johnson LM, Roman CR, Smith AC, Song M, Fleisch JH. Pharmacology of LY315920/S-5920, [[3-(aminooxoacetyl)-2-ethyl-1- (phenylmethyl)-1H-indol-4-yl]oxy] acetate, a potent and selective secretory phospholipase A2 inhibitor: A new class of anti-inflammatory drugs, SPI. J Pharmacol Exp Ther. 1999;288(3):1117-24.