DUAL INHIBITORS OF FATTY ACID AMIDE HYDROLASE AND SOLUBLE EPOXIDE HYDROLASE ENZYMES AS POTENTIAL THERAPEUTICS FOR TREATING PULMONARY FIBROSIS

Fatty acid amide hydrolase (FAAH) is a membrane protein that hydrolyzes endocannabinoids, such as anandamide, which possesses analgesic, anti-inflammatory, and anti-fibrotic properties, resulting in arachidonic acid. Arachidonic acid is involved in pro-inflammatory pathways, such as cyclooxygenase, lipoxygenase, and soluble epoxide hydrolase (sEH) pathways. sEH hydrolyzes anti-inflammatory and anti-fibrotic epoxyeicosatrienoic acids to pro-inflammatory dihydroxyeicosatetraenoic acids.  Designed multiple ligands (DMLs) are small molecules specifically designed to interact with several biological targets involved in multifactorial diseases, such as pain, cancer, Alzheimer’s disease, and pulmonary fibroses. In this project, we used DMLs strategies to design drugs that will simultaneously inhibit sEH and FAAH enzymes which could produce a therapeutic effect for those suffering from idiopathic pulmonary fibrosis and chronic pain related to it. Here using in silico methodologies, microwave-assisted green chemistry synthesis, and in vitro assays, we have designed, synthesized, and biologically evaluated over 60 compounds. In addition, the best inhibitor discovered in this study was evaluated in vivo in a rat model of acute pain. We were able to establish a clear structure-activity relationships and identified benzothiazole and 4-phenylthiazole moieties as the important groups to inhibit these two enzymes in the low nanomolar range as well showing favorable predictions of several pharmacokinetic/pharmacodynamic properties.