Exploitation of Cholane Scaffold for the Discovery of Potent and Selective Farnesoid X Receptor (FXR) and G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1) Ligands

Abstract

Nuclear and G-protein coupled receptors are considered major targets for drug discovery. FXR and GP-BAR1, two bile acid-activated receptors, have gained increasing consideration as druggable receptors. Because endogenous bile acids often target both receptor families, the development of selective ligands has been proven difficult, exposing patients to side effects linked to an unwanted activation of one of the two receptors. In the present study, we describe a novel library of semisynthetic bile acid derivatives obtained by modifications on the cholane scaffold. The pharmacological characterization of this library led to the discovery of 7α-hydroxy-5β-cholan-24-sulfate (7), 6β-ethyl-3α,7β-dihydroxy-5β-cholan-24-ol (EUDCOH, 26), and 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (NorECDCOH, 30) as novel ligands for FXR and GP-BAR1 that might hold utility in the treatment of FXR and GP-BAR1 mediated disorders.

Targeting Bile Acid Receptors: Discovery of a Potent and Selective Farnesoid X Receptor Agonist as a New Lead in the Pharmacological Approach to Liver Diseases

“…Of interest, the above activity decreases with the modification of the configuration at C-3 (compare 2 with the corresponding 3α-azido 6 in Table 1 ) as well as with the introduction of an alcoholic function as side chain end group (compare 2 vs. 3 and 6 vs. 7 in Table 1 ). As expected (Festa et al, 2014), in this subset the configurations at C-6/C-7 as well as the presence of a hydroxyl group at C-7 profoundly affect FXR activation with compounds 1, 4, 5 , and 8 showing a remarkable reduction in term of efficacy in the recruitment of SRC-1 co-activator peptide in Alfa Screen assay. Finally, the corresponding 3-amino derivatives 9–16 did not show any effect in the recruitment assay in the concentration range 20 nM–20 mM.…”

“…Our planned strategy started from methyl 6β-ethyl-7-ketocholanoate 17 ( Figure 3 ), which was prepared following our previously described procedure (Festa et al, 2014). Mesylation at C-3 and subsequent treatment with NaN 3 furnished the 3β-azido derivative 18 as a cornerstone intermediate in the preparation of derivatives 1–4 .…”

“…50–60% that was severe enough to cause drug discontinuation in 40% of patients (Mason et al, 2010). Indeed 6-ECDCA is also a ligand for GPBAR1 (Festa et al, 2014; Pellicciari et al, 2016; Sepe et al, 2016) and therefore the above side effect might be associated to the activation of the membrane BA receptor, recently demonstrated bona fide to be the physiological mediator of itching in mice (Alemi et al, 2013; Lieu et al, 2014). …”

Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa

“…Intestinal complications caused by NSAIDs and coxibs are not prevented by cotreatment with PPIs, and the use of some coxibs is associated with an increased risk of cardiovascular ischemic events. In this context, development of FXR-GP-BAR1 agonists [62,63] to protect the intestinal mucosa might have relevance in the treatment of patients taking ASA or NSAIDs that are at high risk of developing gastrointestinal and cardiovascular complications for whom coxibs cannot be recommended.…”

Farnesoid X receptor modulators (2011 – 2014): a patent review

“…However, at least in animal models, itching caused by subcutaneous administration of OCA requires an intact GPBAR1 signaling [66]. However, further studies are required to clarify the mechanisms of this side effect in clinical settings.…”