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IC50: 9 ± 1 nM or 7.3 x 10-6 mole fraction for sPLA2 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.

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].

Clinical trials: Varespladib methyl, an oral prodrug of LY-315920, effectively reduced LDL-C and inflammatory biomarkers in ACS patients treated with conventional atorvastatin therapy. There were no treatment differences in clinical cardiovascular events

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