title: Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis.
abstract: Autotaxin is a secreted enzyme that catalyzes the conversion of lysophosphatidyl choline into the bioactive lipid mediator lysophosphatidic acid (LPA). It is the primary enzyme responsible for LPA production in plasma. It is upregulated in inflammatory conditions and inhibition of autotaxin may have anti-inflammatory activity in a variety of inflammatory diseases. To determine the role of autotaxin and LPA in the pathophysiology of inflammatory disease states, we used a potent and orally bioavailable inhibitor of autotaxin that we have recently identified, and characterized it in mouse models of inflammation, inflammatory bowel disease (IBD), multiple sclerosis (MS), and visceral pain. Compound-1, a potent inhibitor of autotaxin with an IC50 of ∼2 nM, has good oral pharmacokinetic properties in mice and results in a substantial inhibition of plasma LPA that correlates with drug exposure levels. Treatment with the inhibitor resulted in significant anti-inflammatory and analgesic effects in the carrageenan-induced paw inflammation and acetic acid-induced visceral pain tests, respectively. Compound-1 also significantly inhibited disease activity score in the dextran sodium sulfate-induced model of IBD, and in the experimental autoimmune encephalomyelitis model of MS. In conclusion, the present study demonstrates the anti-inflammatory and analgesic properties of a novel inhibitor of autotaxin that may serve as a therapeutic option for IBD, MS, and pain associated with inflammatory states.
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana kannan@lilly.com.
authors: Kannan
authors: K
authors: Thirunavukkarasu
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Bailin
authors: B
authors: Tan
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Craig A
authors: CA
authors: Swearingen
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Guilherme
authors: G
authors: Rocha
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Hai H
authors: HH
authors: Bui
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Denis J
authors: DJ
authors: McCann
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Spencer B
authors: SB
authors: Jones
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Bryan H
authors: BH
authors: Norman
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Lance A
authors: LA
authors: Pfeifer
authors: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors: Joy K
authors: JK
authors: Saha
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001682:Biological Availability; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D059265:Visceral Pain / Q000188:drug therapy; D000099189:Lysophospholipase D
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D