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  • It has recently been reported that plasma and synovial fluid

    2024-02-19

    It has recently been reported that plasma and synovial fluid levels of autotaxin correlate with severity of knee OA. Synovial fibroblasts isolated from OA patients express significant amounts of autotaxin mRNA, and this increase in autotaxin PS 341 could lead to increased production of LPA, suggesting that autotaxin inhibition could have a therapeutic benefit for OA and other inflammatory states. It is currently not known whether autotaxin inhibition would be efficacious in models of musculoskeletal pain such as those resulting from chemical and surgically induced OA or bone fracture. The goal of this study was to develop novel, highly potent, and orally bioavailable inhibitors of autotaxin with an improved pharmacokinetic profile and determine efficacy in animal models of musculoskeletal pain. In this paper, we describe the development and characterization of compound-1 as a potent inhibitor of autotaxin that shows a dose dependent inhibition of plasma LPA levels in rats and concomitant inhibition of the pain response in various models of musculoskeletal pain, including the mono-sodium iodoacetate (MIA) and meniscal tear models of joint pain and the osteotomy model of bone fracture pain.
    Methods
    Results
    Discussion We used a high throughput screening assay and a plasma assay to identify highly potent and orally bioavailable inhibitors of autotaxin. Using one of these inhibitors (compound-1), we have demonstrated in this study that autotaxin inhibition can provide analgesic benefits in animal models of musculoskeletal pain, including OA and bone fracture pain. The rat MIA model is a commonly used model of pain that has been used to demonstrate analgesic efficacy of compounds targeting various mechanistic pathways26, 27. We have demonstrated that autotaxin inhibition results in a dose dependent inhibition of the hind paw weight bearing differential that serves as a surrogate measure of pain response. There was a 42% inhibition of the pain response at the highest dose tested. The maximal efficacy that can be achieved in the MIA model is dependent on the mechanism being studied and many mechanisms that we have tested usually result in a 25%–50% reduction in the weight bearing differential (unpublished data). Pain inhibition in the hind paw correlated with a decrease in plasma LPA levels observed in the model [Fig. 3(b)]. However, it should be noted that when we did the time course study to correlate LPA levels and pain inhibition, we only observed a loose correlation. There was a 45% inhibition of the pain response at 2 h and a 23% inhibition at 6 h, although the LPA inhibition was fairly equivalent (61% and 50% at the 2 and 6 h time points, respectively). This suggests that local inhibition of LPA in the joint tissues is likely involved in determining efficacy in the model and that the inhibition of plasma LPA can best serve as an easily accessible pharmacodynamic marker of systemic activity of the compound. NSAIDs are commonly prescribed medications for the management of signs and symptoms of OA. However, not all patients get complete pain relief with NSAIDs. We have shown that compound-1 can result in additive pain relief when dosed in combination with the NSAID diclofenac in the MIA model, suggesting the potential utility of an autotaxin inhibitor for patients on background NSAID therapy. A number of OA patients also show decreased/no responsiveness to NSAIDs with prolonged treatment28, 29. We have shown that compound-1 can decrease the pain response in the NSAID non-responding version of the MIA model (in a situation where the NSAID diclofenac had no effect), suggesting that compound-1 may be useful for treating pain in OA patients who do not respond to NSAIDs. The rat meniscal tear model is a well described model of OA where joint destruction and pain occurs after surgical destabilization of the knee joint by transection of the medial collateral ligament and medial meniscus. To confirm that the pain efficacy of compound-1 is not exclusive to the MIA model, we tested it in the rat meniscal tear model and demonstrated a reduction in pain, although dosing for multiple days was needed to see analgesic efficacy. The surgical model is a much more rigorous model to demonstrate efficacy with compounds that target different mechanisms. Even with the NSAID diclofenac, we only see a 25% decrease in weight bearing differential after repeated dosing, and that may be why several doses of the autotaxin inhibitor were needed to see a significant effect of treatment. There is a recent report showing a good correlation between levels of autotaxin in the human knee joint and the severity of OA. It would be interesting to test whether autotaxin inhibition would have a disease modifying effect via preservation of cartilage structure in the meniscal tear model.