PT  - JOURNAL ARTICLE
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
TI  - Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis
AID  - 10.1124/jpet.116.237156
DP  - 2017 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1--13
VI  - 360
IP  - 1
4099  - http://jpet.aspetjournals.org/content/360/1/1.short
4100  - http://jpet.aspetjournals.org/content/360/1/1.full
SO  - J Pharmacol Exp Ther2017 Jan 01; 360
AB  - 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.