Discovery of a novel class of dual GPBAR1 agonists–RORγt inverse agonists for the treatment of IL-17-mediated disorders
Informazioni aggiuntive
Autori
Fiorillo B.,
Roselli R.,
Finamore C.,
Biagioli M.,
Di Giorgio C.,
Bordoni M.,
Conflitti P.,
Marchianò S.,
Bellini R.,
Rapacciuolo P.,
Cassiano C.,
Limongelli V.,
Sepe V.,
Catalanotti B.,
Fiorucci S.,
Zampella A.
Tipo
Articolo pubblicato in rivista scientifica
Anno
2023
Lingua
Inglese
Sommario
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.
Parole chiave
Agonists, Anatomy, Ligands, Receptors, Rodent models
Periodico
ACS Omega
Volume
8
Numero ( Mese )
6
Pagine (o numero dell’articolo)
5983–5994
Diffusione
Licenza
CC BY-NC-ND
Visibilità
Pubblico
Status open access
Green
