Design and synthesis of hyodeoxycholic acid derivatives as GPBAR1 receptor modulators useful in the treatment of colon inflammation

In the context of inflammatory diseases, the Inflammatory Bowel Diseases (IBDs), which include Crohn’s disease (CD) and ulcerative colitis (UC), represent the most common in the worldwide population. The current treatment of IBD includes FANS, corticosteroids, antibiotics, immunosuppressive and anti-TNF- agents.1 However, the limited efficacy of these treatments urges the identification of new therapeutic approaches, as well as the employment of GPBAR1 agonists.2,3 This receptor has an important role in intestinal homeostasis and inflammation-driven immune disfunction. Previous studies have shown that Gpbar1-/- mice have an altered intestinal morphology with increased permeability and higher susceptibility to develop colitis. In addition, in the immune system, GPBAR1 reduces phagocytic activity and the production of pro-inflammatory cytokines (TNF-, IL-1, IL-1, IL-6 and IL-8). Modification on HDCA scaffold afforded to a small library of hyodeoxycholane analogs, as selective and potent GPBAR1 agonists. Our medicinal chemistry strategy has consisted in the introduction of a nitrile group in the side chain and different alkyl, alkenyl or aromatic substituents at C-6 on HDCA. All compounds synthesized have been tested on GPBAR1 receptor through transactivation assays using the hepatic cell line HepG2. Our studies identified compound 6 as potent and selective GPBAR1 agonist (EC50 = 0.3 M), exerting minimal activating effects on the latter receptors. GPBAR1 activation, combined with the ability to revert both the expression of inflammatory genes in vitro and the inflammatory pattern in TNBS-induced colitis model, indicates compound 6 as a promising lead for the treatment of GPBAR1-related inflammatory bowel disorders.