Discovery of new dual GPBAR1 /RORγt modulators with promising activity in the treatment of inflammation diseases

The inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine. The etiology of IBD remains unknown, but its pathogenesis is associated with dysregulated immune responses that drives a persistent inflammatory state within the intestinal mucosa. The clinical course of this disease has shown to be variable and often difficult to manage, increasing the risk of developing colitis-associated cancer. IBD treatment is far from optimal, therefore the discovery of new targets, involved in the inflammatory process, and new chemical entities able to interact with them, represents an appealing therapeutic approach. Several evidences suggest that gastrointestinal homeostasis is strongly dependent on nuclear receptors (NRs) and G protein-coupled receptors (GPCRs) functions, resulting potential drug targets for therapeutic interventions in patients with IBD. In this context, the nuclear retinoic acid-related receptor  (ROR)1,2 and the membrane GPBAR1 receptor3 play a variety of roles ranging from nutrient absorption and transport, sensing of microbial metabolites, to regulation of immune response and intestinal cell integrity. Starting from a consolidated experience in the synthesis of steroidal ligands able to interact with bile acid receptors, several modifications on bile acid scaffold have been performed in order to develop a new class of dual GPBAR1/RORγt modulators. Guided by computational studies (virtual screening, molecular dynamics) and considering that chemical modifications on the bile acid scaffold profoundly influence the pharmacokinetic properties, metabolism, biodistribution and selectivity towards BAs receptors, our medicinal chemistry strategy was focused to obtain new tailored steroidal derivatives. Starting from hyodeoxycholic acid (HDCA), an endogenous bile acid, we have performed some chemical modifications on the steroidal core such us the inversion of the configuration of the hydroxyl group at C-3, the installation of a Δ5 double bond, as well as the introduction of different decorated aromatic rings on the side chain (Figure 1). A deep in vitro and in vivo pharmacological evaluation on a mouse model of induced colitis, led us to identify new chemical entities that could represent novel promising leads for the treatment of gastrointestinal inflammatory processes.