DEVELOPMENT OF MULTI-TARGET DIRECTED LIGANDS FOR THE TREATMENT OF CHRONIC PAIN IN EHLERS-DANLOS SYNDROMES

Ehlers-Danlos Syndromes (EDS) is a group of genetic connective tissue disorders characterized by clinical features such as skin hyperextensibility, joint hypermobility, and tissue fragility. About 90% of EDS patients suffer from chronic pain, which is mainly caused by joint instability and hypermobility. Since EDS is a genetic disorder with no cure, chronic pain in these patients is managed by medications that have negative side effects in long-term use. Fatty acid amide hydrolase (FAAH) is a membrane enzyme that hydrolyzes anandamide, which has anti-inflammatory and analgesic properties, into arachidonic acid (AA). AA is eventually degraded by soluble epoxide hydrolase (sEH) into dihydroxyeicosatrienoic acid (DHET), which is pro-inflammatory. Many animal studies demonstrated that inhibition of FAAH or sEH resulted in antinociception and anti-inflammation. In this project, we seek to develop a compound that can simultaneously inhibit both sEH and FAAH as a potential novel therapeutic for non-opioid chronic pain treatment in EDS. We designed, synthesized, and biologically evaluated 21 compounds. Additionally, we also evaluated 2 compounds in vivo to evaluate toxicity and antinociception. Our SAR study indicates that strong nonpolar electron-withdrawing groups placed in ortho and para positions on the right side of the dual inhibitor are well tolerated. Bulky groups, such as quinoline and thiazole, are tolerated on the left side of the dual inhibitor. In vivo study showed that our dual inhibitor can inhibit pain and does not affect locomotor activities in rats. It also does not bind to any opioid receptor subtypes.