Relevant to this conference he studies the mammalian soluble epoxide hydrolase (sEH) which converts anti-inflammatory, anti-hypertensive and analgesic fatty acid epoxides to their less active and sometimes proinflammatory diols. The sEH is a key enzyme in the cytochrome P450 branch of the arachidonate cascade. After discovering, cloning and expressing the sEH, his laboratory developed potent transition state inhibitors of the enzyme with good oral PK-ADME. These compounds are being examined for several clinical indications including atrial fibrillation, fibrosis and COPD. One IND in this series is on file with the FDA for a sEH inhibitor. Interestingly the pan kinase inhibitors Sorafenib and Regorafenib are low nanomolar inhibitors of the sEH suggesting some of their properties in treating cancer can be attributed to this biochemical action. Currently is laboratory is moving new sEH inhibitors toward the clinic for inflammatory and neuropathic pain. The sEH inhibitors are more potent than NSAIDs on inflammatory pain models and more potent than gabapentin on relieving neuropathic pain in multiple species. For target engagement his laboratory developed a MS based metabolite profiling system allowing quantitative analysis of over 100 lipid mediators including both ω-3 and -6 based fatty acids. This led to the discovery that epoxides of some ω-3 based fatty acids were more anti-inflammatory, anti-hypertensive and analgesic than their ω-6 counter parts. Recent papers show that in rodents ω-6 fatty acid epoxides are mildly angiogenic while ω-3 fatty acid epoxides are strongly anti-angiogenic reducing tumor growth and metastasis.
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