GPBAR1 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-a) in THP1 cells. The binding mode of compound 6 in GPBAR1 was elucidated by docking calculations. Moreover, compound 6 protects against TNBSinduced colitis in Gpbar1+/+ rodent model, representing an intriguing lead for the treatment of these inflammatory disorders.
GPBAR1 activation by C6-substituted hyodeoxycholane analogues protect against colitis / De Marino, S.; Finamore, C.; Biagioli, M.; Carino, A.; Marchiano, S.; Roselli, R.; Di Giorgio, C.; Bordoni, M.; Di Leva, F. S.; Novellino, E.; Cassiano, C.; Limongelli, V.; Zampella, A.; Festa, C.; Fiorucci, S.. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 11:5(2020), pp. 818-824. [10.1021/acsmedchemlett.9b00636]
GPBAR1 activation by C6-substituted hyodeoxycholane analogues protect against colitis
De Marino S.Primo
;Finamore C.;Roselli R.;Di Leva F. S.;Novellino E.;Cassiano C.;Limongelli V.;Zampella A.;Festa C.
;
2020
Abstract
GPBAR1 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-a) in THP1 cells. The binding mode of compound 6 in GPBAR1 was elucidated by docking calculations. Moreover, compound 6 protects against TNBSinduced colitis in Gpbar1+/+ rodent model, representing an intriguing lead for the treatment of these inflammatory disorders.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
