TY - JOUR T1 - Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1 LP - 13 DO - 10.1124/jpet.116.237156 VL - 360 IS - 1 AU - Gretchen Bain AU - Kristen E. Shannon AU - Fei Huang AU - Janice Darlington AU - Lance Goulet AU - Patricia Prodanovich AU - Gina L. Ma AU - Angelina M. Santini AU - Adam J. Stein AU - Dave Lonergan AU - Christopher D. King AU - Imelda Calderon AU - Andiliy Lai AU - John H. Hutchinson AU - Jilly F. Evans Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/360/1/1.abstract N2 - 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 antifibrotic effects in multiple organ systems, including 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 pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic 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 choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH. ER -