Abstract
Multitarget-directed ligands are a promising class of drugs for discovering innovative new therapies for difficult to treat diseases. In this study, we designed dual inhibitors targeting the human fatty acid amide hydrolase (FAAH) enzyme and human soluble epoxide hydrolase (sEH) enzyme. Targeting both of these enzymes concurrently with single target inhibitors synergistically reduces inflammatory and neuropathic pain; thus, dual FAAH/sEH inhibitors are likely to be powerful analgesics. Here, we identified the piperidinyl-sulfonamide moiety as a common pharmacophore and optimized several inhibitors to have excellent inhibition profiles on both targeted enzymes simultaneously. In addition, several inhibitors show good predicted pharmacokinetic properties. These results suggest that this series of inhibitors has the potential to be further developed as new lead candidates and therapeutics in pain management.
Highlights
Pain results from a wide variety of conditions and illnesses
Our structure-activity relationship (SAR) studies showed that the pharmacophore for the soluble epoxide hydrolase (sEH) inhibitors should include a central sulfonamide moiety next to the piperidine ring
The orientation of this amide moiety is similar to the orientation of the urea groups on urea sEH inhibitors (e.g., AUDA, Figure 2); the amide group likely satisfies the same hydrogen bonding interactions with tyrosine and aspartic acid residues that contribute to highly potent urea inhibitors
Summary
Pain results from a wide variety of conditions and illnesses. Managing pain represents a unique challenge to health professionals, which requires multidisciplinary strategies.[1, 2] The most effective analgesic drugs currently used to treat moderate-to-severe pain are opioid agonists (e.g., oxycodone).[3].
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