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      Introduction of Nonacidic Side Chains on 6-Ethylcholane Scaffolds in the Identification of Potent Bile Acid Receptor Agonists with Improved Pharmacokinetic Properties

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          Abstract

          As a cellular bile acid sensor, farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) participate in maintaining bile acid, lipid, and glucose homeostasis. To date, several selective and dual agonists have been developed as promising pharmacological approach to metabolic disorders, with most of them possessing an acidic conjugable function that might compromise their pharmacokinetic distribution. Here, guided by docking calculations, nonacidic 6-ethyl cholane derivatives have been prepared. In vitro pharmacological characterization resulted in the identification of bile acid receptor modulators with improved pharmacokinetic properties.

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          Most cited references 30

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          Identification of a nuclear receptor for bile acids.

          Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism. Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter. These results demonstrate a mechanism by which bile acids transcriptionally regulate their biosynthesis and enterohepatic transport.
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            Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.

            The major metabolic pathway for elimination of cholesterol is via conversion to bile acids. In addition to this metabolic function, bile acids also act as signaling molecules that negatively regulate their own biosynthesis. However, the precise nature of this signaling pathway has been elusive. We have isolated an endogenous biliary component (chenodeoxycholic acid) that selectively activates the orphan nuclear receptor, FXR. Structure-activity analysis defined a subset of related bile acid ligands that activate FXR and promote coactivator recruitment. Finally, we show that ligand-occupied FXR inhibits transactivation from the oxysterol receptor LXR alpha, a positive regulator of cholesterol degradation. We suggest that FXR (BAR) is the endogenous bile acid sensor and thus an important regulator of cholesterol homeostasis.
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              6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity.

              A series of 6alpha-alkyl-substituted analogues of chenodeoxycholic acid (CDCA) were synthesized and evaluated as potential farnesoid X receptor (FXR) ligands. Among them, 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA) was shown to be a very potent and selective FXR agonist (EC(50) = 99 nM) and to be endowed with anticholeretic activity in an in vivo rat model of cholestasis.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                16 March 2019
                March 2019
                : 24
                : 6
                Affiliations
                [1 ]Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy; claudia.finamore@ 123456unina.it (C.F.); giuliana.baronissi@ 123456unina.it (G.B.); francesco.dileva@ 123456unina.it (F.S.D.L.); vittoriolimongelli@ 123456gmail.com (V.L.); azampell@ 123456unina.it (A.Z.)
                [2 ]Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Piazza Lucio Severi, 1 - 06132 Perugia, Italy; silvia4as@ 123456hotmail.it (S.M.); adriana.carino@ 123456hotmail.it (A.C.); stefano.fiorucci@ 123456unipg.it (S.F.)
                [3 ]Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Salerno, Italy; mcmonti@ 123456unisa.it
                [4 ]Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute of Computational Science - Center for Computational Medicine in Cardiology, Via G. Buffi 13, CH-6900 Lugano, Switzerland
                Author notes
                [* ]Correspondence: valentina.sepe@ 123456unina.it ; Tel.: +39-081-678526
                Article
                molecules-24-01043
                10.3390/molecules24061043
                6470523
                30884797
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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