4177374 - Structure-activity relationship studies of 4-phenyl-thiazole moiety on inhibition of soluble epoxide hydrolase and fatty acid amide hydrolase | Poster Board #707

The National Institutes of Health (NIH) describes chronic pain as continuous pain persisting from months to years that affects and limits an individual’s physical activity. The prescription pain medicines such as opioids are being used to manage chronic pain. However, the continuous use of opioids can lead to a dependence, addiction, and even death due to overdose. The long-term goal of our lab is to discover opioid alternatives for the chronic pain treatment. In our lab we previously discovered several potent dual inhibitors of enzymes, soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), both involved in pain and inflammation. Our most potent dual inhibitor possesses 4-phenyl-thiazole moiety, showed moderate stability in human and rat plasma, and alleviates pain in vivo. Here we performed structure-activity relationship studies of the 4-phenyl-thiazole part by testing importance of the methoxy groups on the dual sEH/FAAH inhibition. We first designed compounds using in silico tools to predict several important pharmacokinetic properties. All new analogs are predicted not to cross Blood Brain Barrier and to be more metabolically stable than the lead compound. Using a four-step synthetic route, we synthesized the target analogs. We first obtained different methoxy-4-phenyl-thiazole anilines using microwave-assisted Hantzsch-thiazole reaction. This aniline was coupled to the carboxylic acid intermediate using EDC-peptide coupling conditions in the moderate yields. All new analogs were screened in human, mouse and rat sEH and human FAAH enzymatic inhibition assays. We observed that methoxy group was well-tolerated in both enzymes, yielding inhibitors in nanomolar range. The best compound will be scaled up and tested for stability in liver microsomal assays and in vivo.