title: Identification and pharmacological characterization of a novel inhibitor of autotaxin in rodent models of joint pain.
abstract: Autotaxin is a secreted lysophospholipase that mediates the conversion of lysophosphatidyl choline (LPC) to lysophosphatidic acid (LPA), a bioactive lipid mediator. Autotaxin levels in plasma and synovial fluid correlate with disease severity in patients with knee osteoarthritis (OA). The goal of this study was to develop and characterize a novel small molecule inhibitor of autotaxin to inhibit LPA production in vivo and determine its efficacy in animal models of musculoskeletal pain.
  
  
  
  Compound libraries were screened using an LPC coupled enzyme assay that measures the amount of choline released from LPC by the action of autotaxin. Hits from this assay were tested in a plasma assay to assess inhibition of endogenous plasma autotaxin and subsequently tested for their ability to lower plasma LPA levels upon oral dosing of rats. The best compounds were then tested in animal models of musculoskeletal pain.
  
  
  
  Compound screening led to the identification of compounds with nanomolar potency for inhibition of autotaxin activity. Studies in rats demonstrated a good correlation between compound exposure levels and a decrease in LPA levels in plasma. The leading molecule (compound-1) resulted in a dose dependent decrease in joint pain in the mono-sodium iodoacetate (MIA) and meniscal tear models and a decrease in bone fracture pain in the osteotomy model in rats.
  
  
  
  We have identified and characterized a novel small molecule inhibitor of autotaxin and demonstrated its efficacy in animal models of musculoskeletal pain. The inhibitor has the potential to serve as an analgesic for human OA and bone fracture.
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: kannan@lilly.com.
authors.forename: K
authors.initials: K
authors.lastname: Thirunavukkarasu
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Swearingen
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Oskins
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lin
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Bui
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Jones
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Pfeifer
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: B H
authors.initials: BH
authors.lastname: Norman
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Mitchell
authors.affiliation: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: markgchambers@gmail.com.
authors.forename: M G
authors.initials: MG
authors.lastname: Chambers
mesh_terms: D000818:Animals; D018771:Arthralgia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D004285:Dogs; D006801:Humans; D019807:Iodoacetic Acid / Q000633:toxicity; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D008592:Menisci, Tibial / Q000601:surgery; D020370:Osteoarthritis, Knee / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D010027:Osteotomy; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D000070600:Tibial Meniscus Injuries; D000099189:Lysophospholipase D
chemical_list: D019807:Iodoacetic Acid; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid
keywords: Autotaxin; LPA; Meniscal tear; Mono-sodium iodoacetate (MIA); NSAIDs; Pain