Title Page Selective Inhibition of Autotaxin is Efficacious in Mouse Models of Liver Fibrosis

Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound anti-fibrotic effects in multiple organ systems including the lung, kidney, skin and peritoneum. However, other LPA-generating pathways exist and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacological, pharmacokinetic and pharmacodynamic properties of a novel small-molecule ATX inhibitor [3((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2fluorobenzoic acid sodium salt] (PAT-505). PAT-505 is a potent, selective, non-competitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a STAMTM model of non-alcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small, but significant, improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a cholinedeficient high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning and inflammation. These data demonstrate that inhibiting autotaxin is anti-fibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on October 17, 2016 as DOI: 10.1124/jpet.116.237156 at A PE T Jornals on O cber 6, 2016 jpet.asjournals.org D ow nladed from