Vol. 288, Issue 3, 1117-1124, March 1999

Pharmacology of LY315920/S-5920,¹ [[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

David W. Snyder, Nicholas J. Bach, Robert D. Dillard, Susan E. Draheim, Donald G. Carlson, Niles Fox, Neal W. Roehm, Christopher T. Armstrong, Chan H. Chang, Lawrence W. Hartley, Lea M. Johnson, Carlos R. Roman, Amy C. Smith, Min Song and Jerome H. Fleisch

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana

LY315920 is a potent, selective inhibitor of recombinant human, group IIA, nonpancreatic secretory PLA₂ (sPLA₂). In a chromogenic isolated enzyme assay, LY315920 inhibited sPLA₂ activity with an IC₅₀ of 9 ± 1 nM or 7.3 × 10⁶ 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 × 10⁶. 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.