GPBAR1 Activation by C6-Substituted Hyodeoxycholane Analogues Protect against Colitis

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 Fiorucci

doi:10.1021/acsmedchemlett.9b00636

GPBAR1 Activation by C6-Substituted Hyodeoxycholane Analogues Protect against Colitis

ACS Med Chem Lett. 2020 Mar 2;11(5):818-824. doi: 10.1021/acsmedchemlett.9b00636. eCollection 2020 May 14.

Authors

Simona De Marino¹, Claudia Finamore¹, Michele Biagioli², Adriana Carino², Silvia Marchianò², Rosalinda Roselli¹, Cristina Di Giorgio², Martina Bordoni², Francesco Saverio Di Leva¹, Ettore Novellino¹, Chiara Cassiano¹, Vittorio Limongelli^{1

3}, Angela Zampella¹, Carmen Festa¹, Stefano Fiorucci²

Affiliations

¹ Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, 80131 Naples, Italy.
² Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Perugia CH-6900, Italy.
³ Faculty of Biomedical Sciences, Institute of Computational Science, Center for Computational Medicine in Cardiology, Università della Svizzera italiana (USI), Via G. Buffi 13, CH-6900 Lugano, Switzerland.

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-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.