Abstract

LY315920 is a potent, selective inhibitor of recombinant human, group IIA, nonpancreatic secretory PLA₂ (sPLA₂). In a chromogenic isolated enzyme assay, LY315920 inhibited sPLA₂activity with an IC₅₀ of 9 ± 1 nM or 7.3 × 10⁻⁶ mole fraction, which approached the stiochiometric limit of this assay. The true potency of LY315920 was defined using a deoxycholate/phosphatidylcholine assay with a mole fraction of 1.5 × 10⁻⁶. LY315920 was 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 release of thromboxane A₂ (TXA₂) from isolated guinea pig lung bronchoalveolar lavage cells was inhibited by LY315920 with an IC₅₀ of 0.79 μM. The release of TXA₂ from these cells by N-formyl-methionyl-leucyl-phenylalanine or arachidonic acid was not inhibited. The i.v. administration of LY315920, 5 min before harvesting the bronchoalveolar lavage cells, resulted in the inhibition of sPLA₂-induced production of TXA₂ with an ED₅₀ of 16.1 mg/kg. Challenge of guinea pig lung pleural strips with sPLA₂ produced contractile responses that were suppressed in a concentration-dependent manner by LY315920 with an apparent K_B of 83 ± 14 nM. Contractile responses induced by arachidonic acid were not altered. Intravenous or oral administration of LY315920 to transgenic mice expressing the human sPLA₂ protein inhibited serum sPLA₂ activity in a dose-related manner over a 4-h time course. LY315920 is a potent and selective sPLA₂ inhibitor and represents a new class of anti-inflammatory agent designated SPI. This agent is currently undergoing clinical evaluation and should help to define the role of sPLA₂ in various inflammatory disease states.