2. Academic Validation
  3. An adamantylureido-benzylamide aniline as FLAP/sEH dual inhibitor: Rational design, in vitro and in vivo lipidomic profiling

An adamantylureido-benzylamide aniline as FLAP/sEH dual inhibitor: Rational design, in vitro and in vivo lipidomic profiling

  • Eur J Med Chem. 2026 Jan 15;302(Pt 2):118338. doi: 10.1016/j.ejmech.2025.118338.
Tania Ciaglia 1,  Danilo D'Avino 2,  Paul M Jordan 3,  Simone Di Micco 4,  Simona Musella 1,  Hannes Engelbrecht 3,  Lukas Klaus Peltner 3,  Veronica Di Sarno 1,  Fabrizio Merciai 1,  Sara Perna 2,  Gerardina Smaldone 1,  Francesca Di Matteo 1,  Valeria Napolitano 1,  Rosario Stimoli 5,  Giuseppe Bifulco 1,  Giacomo Pepe 1,  Eduardo Maria Sommella 1,  Manuela Giovanna Basilicata 6,  Giovanna Aquino 7,  Isabel M Gomez-Monterrey 2,  Pietro Campiglia 1,  Carmine Ostacolo 1,  Oliver Werz 3,  Antonietta Rossi 8,  Alessia Bertamino 9,  Michele Manfra 10
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, Fisciano, Salerno, Italy, 84084.
  • 2 Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy.
  • 3 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743, Jena, Germany.
  • 4 European Biomedical Research Institute of Salerno (EBRIS), Via S. De Renzi 50, 84125, Salerno, Italy.
  • 5 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, Fisciano, Salerno, Italy, 84084; National PhD Program in "RNA Therapeutics and Gene Therapy", Napoli, Italy.
  • 6 Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", P.zza L. Miraglia, 2, 80138, Naples, Italy.
  • 7 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, Fisciano, Salerno, Italy, 84084; AREA Science Park, Laboratorio di Multi-omica Area Sud (LAAS), Baronissi, Salerno, 84081, Italy.
  • 8 Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy. Electronic address: [email protected].
  • 9 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, Fisciano, Salerno, Italy, 84084. Electronic address: [email protected].
  • 10 Department of Science, University of Basilicata, Via Dell'Ateneo Lucano 10, Potenza, 85100, Italy.
PMID: 41197472 DOI: 10.1016/j.ejmech.2025.118338
Abstract

Multitarget approaches are highly effective strategies for treating acute and chronic inflammatory diseases. In this field, the dual inhibition of 5-lipoxygenase-activating protein (FLAP) and soluble Epoxide Hydrolase (sEH) offers the advantage of reducing the production of diverse pro-inflammatory lipid mediators (LMs) while preserving pro-resolving mediator levels. However, this approach is underexplored in medicinal chemistry, given the limited number of existing dual inhibitors. Here, we present the rational design of the adamantylureido-benzylamide aniline 6, which features in vitro FLAP/sEH inhibitory activity. An accurate investigation about the crucial interactions between our synthesized derivatives and 5LOX, FLAP and sEH binding sites, led us to shed light on structural requirements differentiating among the three targets. Lipidomic profiling following 6in vivo administration highlighted the reduction of 5-LOX/FLAP- and sEH-derived LMs, resulting in a favourable redistribution of LMs in agreement with the inhibition of its molecular targets.

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