Pharmacology of LY315920/S-5920, [[3-(aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetate, a potent and selective secretory phospholipase A(2) inhibitor: A new class of anti-inflammatory drugs, SPI

LY315920 is a potent, selective inhibitor of recombinant human, group IIA, nonpancreatic secretory PLA(2) (sPLA(2)). In a chromogenic isolated enzyme assay, LY315920 inhibited sPLA(2) activity with an IC50 of 9 +/- 1 nM or 7. 3 x 10(-6) mole fraction, which approached the stiochiometric limit of this assay. The true potency of LY315920 was defined using a deoxycholate/phosp hatidylcholine assay with a mole fraction of 1.5 x 10(-6). LY315920 was 40- fold less active against human, group IB, pancreatic sPLA(2) and was inacti ve against cytosolic PLA(2) and the constitutive and inducible forms of cyc looxygenase. Human sPLA(2)-induced release of thromboxane A(2) (TXA(2)) fro m isolated guinea pig lung bronchoalveolar lavage cells was inhibited by LY 315920 with an IC50 of 0.79 mu M. The release of TXA(2) from these cells by N-formyl-methionyl-leucyl-phenytalanine or arachidonic acid was not inhibi ted. The i.v. administration of LY315920, 5 min before harvesting the bronc hoalveolar lavage cells, resulted in the inhibition of sPLA(2)-induced prod uction of TXA(2) with an ED50 of 16.1 mg/kg. Challenge of guinea pig lung p leural strips with sPLA(2) produced contractile responses that were suppres sed in a concentration-dependent manner by LY315920 with an apparent K-B of 83 +/- 14 nM. Contractile responses induced by arachidonic acid were not a ltered. Intravenous or oral administration of LY315920 to transgenic mice e xpressing the human sPLA(2) protein inhibited serum sPLA(2) activity in a d ose-related manner over a 4-h time course. LY315920 is a potent and selecti ve sPLA(2) 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 sPLA(2) in various inflammatory disease s tates.