2. Academic Validation
  3. Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions

Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions

  • Eur J Med Chem. 2023 Jan 15:246:114952. doi: 10.1016/j.ejmech.2022.114952.
Alessandro Papa 1,  Silvia Pasquini 2,  Francesca Galvani 3,  Mariarosaria Cammarota 4,  Chiara Contri 5,  Gabriele Carullo 6,  Sandra Gemma 1,  Anna Ramunno 7,  Stefania Lamponi 1,  Beatrice Gorelli 6,  Simona Saponara 6,  Katia Varani 5,  Marco Mor 8,  Giuseppe Campiani 1,  Francesca Boscia 4,  Fabrizio Vincenzi 5,  Alessio Lodola 3,  Stefania Butini 9
Affiliations

Affiliations

  • 1 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.
  • 2 Dipartimento di Scienze Chimiche, Farmaceutiche e Agrarie, Università degli Studi di Ferrara, Via Borsari 46, 44121, Ferrara, Italy.
  • 3 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy.
  • 4 Divisione di Farmacologia, Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Università degli Studi di Napoli Federico II, Via Pansini 5, 80131, Napoli, Italy.
  • 5 Dipartimento di Medicina Traslazionale, Università degli Studi di Ferrara, Via Borsari 46, 44121, Ferrara, Italy.
  • 6 Dipartiment di Scienze della Vita, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.
  • 7 Dipartimento di Farmacia, Università degli Studi di Salerno, Viale Giovanni Paolo II 132, 84084, Fisciano (SA), Italy.
  • 8 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124, Parma, Italy; Microbiome Research Hub, Università degli Studi di Parma, Parco Area delle Scienze 11/A, I-43124, Parma, Italy.
  • 9 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy. Electronic address: [email protected].
PMID: 36462439 DOI: 10.1016/j.ejmech.2022.114952
Abstract

The neuroprotective performance against neuroinflammation of the endocannabinoid system (ECS) can be remarkably improved by indirect stimulation mediated by the pharmacological inhibition of the key ECS catabolic enzyme fatty acid amide hydrolase (FAAH). Based on our previous works and aiming to discover new selective FAAH inhibitors , we herein reported a new series of carbamate-based FAAH inhibitors (4a-t) which showed improved drug disposition properties compared to the previously reported analogues 2a-b. The introduction of ionizable functions allowed us to obtain new FAAH inhibitors of nanomolar potency characterized by good water solubility and chemical stability at physiological pH. Interesting structure-activity relationships (SARs), deeply analyzed by molecular docking and molecular dynamic (MD) simulations, were obtained. All the newly developed inhibitors showed an excellent selectivity profile evaluated against monoacylglycerol Lipase and cannabinoid receptors. The reversible mechanism of action was determined by a rapid dilution assay. Absence of toxicity was confirmed in mouse fibroblasts NIH3T3 (for compounds 4e, 4g, 4n-o, and 4s) and in human astrocytes cell line 1321N1 (for compounds 4e, 4n, and 4s). The absence of undesired cardiac effects was also confirmed for compound 4n. Selected analogues (compounds 4e, 4g, 4n, and 4s) were able to reduce oxidative stress in 1321N1 astrocytes and exhibited notable neuroprotective effects when tested in an ex vivo model of neuroinflammation.

Keywords

Endocannabinoid system; Enzyme inhibitors; Fatty acid amide hydrolase; Neuroinflammation; Neuroprotection; Reversible inhibitors; Selective inhibitors.

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