title: Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis.
abstract: 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.
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.) gbain@pharmakea.com.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Bain
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Shannon
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Janice
authors.initials: J
authors.lastname: Darlington
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Lance
authors.initials: L
authors.lastname: Goulet
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Patricia
authors.initials: P
authors.lastname: Prodanovich
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Gina L
authors.initials: GL
authors.lastname: Ma
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Angelina M
authors.initials: AM
authors.lastname: Santini
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Stein
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Dave
authors.initials: D
authors.lastname: Lonergan
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Christopher D
authors.initials: CD
authors.lastname: King
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Imelda
authors.initials: I
authors.lastname: Calderon
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Andiliy
authors.initials: A
authors.lastname: Lai
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: John H
authors.initials: JH
authors.lastname: Hutchinson
authors.affiliation: PharmAkea Inc, San Diego, California (G.B., K.E.S., F.H., J.D., L.G., P.P., G.L.M., A.M.S., D.L., C.D.K., I.C., A.L., J.H.H., J.E.F.); Cayman Chemical Company, Ann Arbor, Michigan (A.J.S.).
authors.forename: Jilly F
authors.initials: JF
authors.lastname: Evans
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000099189:Lysophospholipase D
chemical_list: D004791:Enzyme Inhibitors; D010727:Phosphoric Diester Hydrolases; D010879:Piperazines; D000099189:Lysophospholipase D