Design, synthesis, molecular modeling and biological activity of chenodeoxycholic acid carbamate derivatives as potent and selective FXR agonists

The FXR receptor is an interesting subject for chemical and biological investigation because of the peculiar structural features of its ligand binding domain and the therapeutic potential for the treatment of liver and metabolic diseases involved in its modulation.1 Within an intense study of structure-activity relationship to define the role of the side chain of bile acids in terms of potency and activity against the receptor,2 was synthesized the 23-N-(carbocinnamyloxy)-3,7-dihydroxy-6-ethyl-24-nor-5-cholan-23-amine (Figure 1). After alphascreen assays and PCR-RT had been shown that this derivative was a powerful and especially selective agonist against FXR. This result was an excellent starting point for studying the mechanisms of receptor activation as it had emphasized the important role of the 6-ethyl group in stabilizing the bioactive conformation of FXR and the possibility of a relationship between the elements of LBD known to influence the binding of coactivators and the receptor's back door, localized between loops H1- H2 and H4-H5.3 In addition with this result this compound was an excellent tool for chemical studies in vitro and in vivo. It’s necessary, however, in view of in vivo and therapeutic application, consider the physico-chemical properties and the pharmacokinetic and metabolic characteristics of the compound. Therefore in this study we report the design, synthesis, molecular modeling studies and biological evaluations of a series of 6a-ethyl-24-nor-cholanylamine derivatives, synthesized to improve the solubility and metabolic stability of the 23-N-(carbocinnamyloxy)-3,7-dihydroxy-6-ethyl-24-nor-5-cholan-23-amine.