VARESPLADIB

Uses

Varespladib has been used as a secretory phospholipase A (sPLA2) inhibitor:

• to test its effect on the human astrocytes subjected to psychosine-induced toxicity
• to test its neutralization functionality on the black snake species P. colletti?venom
• in combination with snake venom metalloproteinases (SVMP)-inhibitor, marimastat to test its protective functionality on envenoming by vipers

Uses

VARESPLADIB is used as a PLA2 inhibitor (Phospholipase A2 Enzyme inhibitor).

Definition

ChEBI: Varespladib is a member of the class of indoles that is 1H-indole substituted by benzyl, ethyl, oxamoyl, and carboxymethoxy groups at positions 1, 2, 3, and 4, respectively. It is an oral secretory phospholipase A2 inhibitor and exhibits anti-inflammatory effects. It has a role as an EC 3.1.1.4 (phospholipase A2) inhibitor, an anti-inflammatory drug and an antidote. It is a member of indoles, a member of benzenes, an aromatic ether, a dicarboxylic acid monoamide, a monocarboxylic acid and a primary carboxamide. It is a conjugate acid of a varespladib(1-).

Biological Activity

phospholipases (plas) produce rate-limiting precursors in the various types of biologically active lipid biosynthesis. increased levels of human nonpancreatic secretory phospholipase a2 (hnps-pla2) have been detected in several pathological conditions. ly315920 was selected for evaluation clinically as an hnps-pla2 inhibitor.

Biochem/physiol Actions

Varespladib is effective against viper and elapid venoms and is used in snakebite therapy. It is reported to interact with the hydrophobic channel of the PLA2-like toxin in in vitro structural studies. It blocks inflammatory cascades related to the sPLA2.

in vitro

the true potency of ly315920 was defined to be a mole fraction of 1.5 x 10-6 using a deoxycholate/phosphatidylcholine assay. ly315920 was found to be 40-fold less active against human, group ib, pancreatic spla2 and was inactive against cytosolic pla2 and the constitutive and inducible forms of cyclooxygenase. human spla2-induced thromboxane a2 release from isolated guinea pig lung bronchoalveolar lavage cells was inhibited by ly315920 with the ic50 of 0.79 μm [1].

in vivo

the i.v. administration of ly315920, 5 min before the bronchoalveolar lavage cells harvest, led to the inhibition of spla2-induced production of txa2 with an ed50 of 16.1 mg/kg. [2].

IC 50

9 ± 1 nm or 7.3 x 10-6 mole fraction for spla2 activity

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.
[2] rosenson rs, hislop c, elliott m, stasiv y, goulder m, waters d. effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients. j am coll cardiol. 2010;56(14):1079-88.