ml9b00636_si_001.pdf (1.35 MB)
GPBAR1 Activation by C6-Substituted Hyodeoxycholane Analogues Protect against Colitis
journal contribution
posted on 2020-03-05, 21:43 authored by Simona
De Marino, Claudia Finamore, Michele Biagioli, Adriana Carino, Silvia Marchianò, Rosalinda Roselli, Cristina Di Giorgio, Martina Bordoni, Francesco Saverio Di Leva, Ettore Novellino, Chiara Cassiano, Vittorio Limongelli, Angela Zampella, Carmen Festa, Stefano FiorucciGPBAR1 agonists have
been identified as potential leads for the
treatment of diseases related to colon inflammation such as Crohn’s
and ulcerative colitis. In this paper, we report the discovery of
a small library of hyodeoxycholane analogues, decorated at C-6 with
different substituents, as potent and selective GPBAR1 agonists. In vitro pharmacological assays showed that compound 6 selectively activates GPBAR1 (EC50 = 0.3 μM)
and reduces the production of pro-inflammatory cytokines (IL-1β,
IL-6, and TNF-α) in THP1 cells. The binding mode of compound 6 in GPBAR1 was elucidated by docking calculations. Moreover,
compound 6 protects against TNBS-induced colitis in Gpbar1+/+ rodent model, representing an intriguing lead for the treatment
of these inflammatory disorders.
