Discovery of a novel class of dual GPBAR1 agonists–RORγt inverse agonists for the treatment of IL-17-mediated disorders
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Fiorillo, Bianca
Department of Pharmacy, University of Naples "Federico II", Naples, Italy
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Roselli, Rosalinda
Department of Pharmacy, University of Naples "Federico II", Naples, Italy
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Finamore, Claudia
Department of Pharmacy, University of Naples "Federico II", Naples, Italy
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Biagioli, Michele
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Di Giorgio, Cristina
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Bordoni, Martina
Precision BioTherapeutics, Perugia, Italy
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Conflitti, Paolo
Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Marchianò, Silvia
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Bellini, Rachele
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Rapacciuolo, Pasquale
Department of Pharmacy, University of Naples "Federico II", Naples, Italy
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Cassiano, Chiara
Department of Pharmacy, University of Naples "Federico II", Naples, Italy
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Limongelli, Vittorio
ORCID
Department of Pharmacy, University of Naples "Federico II", Naples, Italy - Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Sepe, Valentina
ORCID
Department of Pharmacy, University of Naples "Federico II", Naples, Italy
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Catalanotti, Bruno
ORCID
Department of Pharmacy, University of Naples "Federico II", Naples, Italy
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Fiorucci, Stefano
Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Zampella, Angela
ORCID
Department of Pharmacy, University of Naples "Federico II", Naples, Italy
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Published in:
- ACS Omega. - 2023, vol. 8, no. 6, p. 5983–5994
English
Retinoic acid receptor-related orphan receptor γ-t (RORγt) and GPBAR1, a transmembrane G-protein-coupled receptor for bile acids, are attractive drug targets to develop clinically relevant small modulators as potent therapeutics for autoimmune diseases. Herein, we designed, synthesized, and evaluated several new bile acid-derived ligands with potent dual activity. Furthermore, we performed molecular docking and MD calculations of the best dual modulators in the two targets to identify the binding modes as well as to better understand the molecular basis of the inverse agonism of RORγt by bile acid derivatives. Among these compounds, 7 was identified as a GPBAR1 agonist (EC50 5.9 μM) and RORγt inverse agonist (IC50 0.107 μM), with excellent pharmacokinetic properties. Finally, the most promising ligand displayed robust anti-inflammatory activity in vitro and in vivo in a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis.
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Medicine
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CC BY-NC-ND
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green
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https://n2t.net/ark:/12658/srd1328338
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