Development of multitarget inhibitors for the treatment of pain: Design, synthesis, biological evaluation and molecular modeling studies
Stephanie Wilt, Sean D. Kodani, Thanh N. H. Le, Lato Nguyen, Nghi Vo, Tanya Ly, Mark Anthony Rodriguez, P. K. Hudson, Christophe Morisseau, Bruce D. Hammock, Stevan Pecic
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.