Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.


The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Your Environment. Your Health.

Publication Detail

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 Exiting the NIEHS site

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*

to Top