RT Journal Article SR Electronic T1 A Novel Autotaxin Inhibitor Reduces Lysophosphatidic Acid Levels in Plasma and the Site of Inflammation JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.110.165845 DO 10.1124/jpet.110.165845 A1 James K. Gierse A1 Atli Thorarensen A1 Konstantine Beltey A1 Erica Bradshaw-Pierce A1 Luz Cortes-Burgos A1 Troii Hall A1 Amy Johnston A1 Michael Murphy A1 Olga Nemirovskiy A1 Shinji Ogawa A1 Lyle Pegg A1 Matthew Pelc A1 Michael Prinsen A1 Mark Schnute A1 Jay Wendling A1 Steve Wene A1 Robin Weinberg A1 Authur Wittwer A1 Ben Zweifel A1 Jaime Masferrer YR 2010 UL http://jpet.aspetjournals.org/content/early/2010/04/14/jpet.110.165845.abstract AB Autotaxin is the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC) and is upregulated in many inflammatory conditions, including but not limited to cancer, arthritis and multiple sclerosis. LPA signaling causes angiogenesis, mitosis, cell proliferation and cytokine secretion. Inhibition of autotaxin may have anti-inflammatory properties in a variety of diseases, however, this hypothesis has not been tested pharmacologically due to the lack of potent inhibitors. Here we report the development of a potent autotaxin inhibitor (PF-8380) with an IC50 of 2.8 nM in isolated enzyme assay and 101 nM inhuman whole blood. PF-8380 has adequate oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Autotaxin's role to produce LPA in plasma and at the site of inflammation was tested in a rat air pouch model. The specific inhibitor PF-8380, dosed orally at 30 mg/kg, provided > 95% reduction in both plasma and air pouch LPA within 3 hours, indicating autotaxin is a major source of LPA during inflammation. 30 mg/kg PF-8380 reduced inflammatory pain with the same maximal efficacy as naproxen. Inhibition of plasma autotaxin activity correlated with inhibition of autotaxin at the site of inflammation and in ex vivo whole blood. Furthermore a close PK/PD relationship was observed, which suggests that LPA is rapidly formed and degraded in vivo. PF-8380 can serve as a tool compound to elucidate LPA's role in inflammation.The American Society for Pharmacology and Experimental Therapeutics