Discovery of a novel class of dual GPBAR1 agonists–RORγt inverse agonists for the treatment of IL-17-mediated disorders

Fiorillo, Bianca; Roselli, Rosalinda; Finamore, Claudia; Biagioli, Michele; Di Giorgio, Cristina; Bordoni, Martina; Conflitti, Paolo; Marchianò, Silvia; Bellini, Rachele; Rapacciuolo, Pasquale; Cassiano, Chiara; Limongelli, Vittorio; Sepe, Valentina; Catalanotti, Bruno; Fiorucci, Stefano; Zampella, Angela

doi:10.1021/acsomega.2c07907

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Journal article

Discovery of a novel class of dual GPBAR1 agonists–RORγt inverse agonists for the treatment of IL-17-mediated disorders

Fiorillo, Bianca Department of Pharmacy, University of Naples "Federico II", Naples, Italy
Roselli, Rosalinda Department of Pharmacy, University of Naples "Federico II", Naples, Italy
Finamore, Claudia Department of Pharmacy, University of Naples "Federico II", Naples, Italy
Biagioli, Michele Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Di Giorgio, Cristina Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Bordoni, Martina Precision BioTherapeutics, Perugia, Italy
Conflitti, Paolo Euler Institute (EUL), Università della Svizzera italiana, Switzerland
Marchianò, Silvia Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Bellini, Rachele Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Rapacciuolo, Pasquale Department of Pharmacy, University of Naples "Federico II", Naples, Italy
Cassiano, Chiara Department of Pharmacy, University of Naples "Federico II", Naples, Italy
Limongelli, Vittorio ORCID Department of Pharmacy, University of Naples "Federico II", Naples, Italy - Euler Institute (EUL), Università della Svizzera italiana, Switzerland
Sepe, Valentina ORCID Department of Pharmacy, University of Naples "Federico II", Naples, Italy
Catalanotti, Bruno ORCID Department of Pharmacy, University of Naples "Federico II", Naples, Italy
Fiorucci, Stefano Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Zampella, Angela ORCID Department of Pharmacy, University of Naples "Federico II", Naples, Italy

2023

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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