Title: Further exploration of the structure-activity relationship of dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors.

Authors: Wilt, Stephanie; Kodani, Sean; Valencia, Leah; Hudson, Paula K; Sanchez, Stephanie; Quintana, Taylor; Morisseau, Christophe; Hammock, Bruce D; Kandasamy, Ram; Pecic, Stevan

Published In Bioorg Med Chem, (2021 Dec 01)

Abstract: Fatty acid amide hydrolase (FAAH) is a membrane protein that hydrolyzes endocannabinoids, and its inhibition produces analgesic and anti-inflammatory effects. The soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids. EETs have anti-inflammatory and inflammation resolving properties, thus inhibition of sEH consequently reduces inflammation. Concurrent inhibition of both enzymes may represent a novel approach in the treatment of chronic pain. Drugs with multiple targets can provide a superior therapeutic effect and a decrease in side effects compared to ligands with single targets. Previously, microwave-assisted methodologies were employed to synthesize libraries of benzothiazole analogs from which high affinity dual inhibitors (e.g. 3, sEH IC50 = 9.6 nM; FAAH IC50 = 7 nM) were identified. Here, our structure-activity relationship studies revealed that the 4-phenylthiazole moiety is well tolerated by both enzymes, producing excellent inhibition potencies in the low nanomolar range (e.g. 6o, sEH IC50 = 2.5 nM; FAAH IC50 = 9.8 nM). Docking experiments show that the new class of dual inhibitors bind within the catalytic sites of both enzymes. Prediction of several pharmacokinetic/pharmacodynamic properties suggest that these new dual inhibitors are good candidates for further in vivo evaluation. Finally, dual inhibitor 3 was tested in the Formalin Test, a rat model of acute inflammatory pain. The data indicate that 3 produces antinociception against the inflammatory phase of the Formalin Test in vivo and is metabolically stable following intraperitoneal administration in male rats. Further, antinociception produced by 3 is comparable to that of ketoprofen, a traditional nonsteroidal anti-inflammatory drug. The results presented here will help toward the long-term goal of developing novel non-opioid therapeutics for pain management.

PubMed ID: 34794001

MeSH Terms: Acute Pain/chemically induced; Acute Pain/drug therapy; Acute Pain/metabolism; Amidohydrolases/antagonists & inhibitors*; Amidohydrolases/metabolism; Animals; Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal/chemistry; Anti-Inflammatory Agents, Non-Steroidal/pharmacology*; Dose-Response Relationship, Drug; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/pharmacology*; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/metabolism; Formaldehyde; Inflammation/chemically induced; Inflammation/drug therapy; Inflammation/metabolism; Male; Molecular Docking Simulation; Molecular Structure; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiazoles/chemical synthesis; Thiazoles/chemistry; Thiazoles/pharmacology*