PT  - JOURNAL ARTICLE
AU  - James Gierse
AU  - Atli Thorarensen
AU  - Konstantine Beltey
AU  - Erica Bradshaw-Pierce
AU  - Luz Cortes-Burgos
AU  - Troii Hall
AU  - Amy Johnston
AU  - Michael Murphy
AU  - Olga Nemirovskiy
AU  - Shinji Ogawa
AU  - Lyle Pegg
AU  - Matthew Pelc
AU  - Michael Prinsen
AU  - Mark Schnute
AU  - Jay Wendling
AU  - Steve Wene
AU  - Robin Weinberg
AU  - Arthur Wittwer
AU  - Ben Zweifel
AU  - Jaime Masferrer
TI  - A Novel Autotaxin Inhibitor Reduces Lysophosphatidic Acid Levels in Plasma and the Site of Inflammation
AID  - 10.1124/jpet.110.165845
DP  - 2010 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 310--317
VI  - 334
IP  - 1
4099  - http://jpet.aspetjournals.org/content/334/1/310.short
4100  - http://jpet.aspetjournals.org/content/334/1/310.full
SO  - J Pharmacol Exp Ther2010 Jul 01; 334
AB  - Autotaxin is the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC), and it is up-regulated 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 because of the lack of potent inhibitors. Here, we report the development of a potent autotaxin inhibitor, PF-8380 [6-(3-(piperazin-1-yl)propanoyl)benzo[d]oxazol-2(3H)-one] with an IC50 of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood. PF-8380 has adequate oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Autotaxin's role in producing 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 h, indicating autotaxin is a major source of LPA during inflammation. At 30 mg/kg PF-8380 reduced inflammatory hyperalgesia with the same efficacy as 30 mg/kg 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 pharmacokinetic/pharmacodynamic relationship was observed, which suggests that LPA is rapidly formed and degraded in vivo. PF-8380 can serve as a tool compound for elucidating LPA's role in inflammation. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics