BAR502/fibrate conjugates: synthesis, biological evaluation and metabolic profile

BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we report the synthesis and the biological evaluation of a library of hybrid compounds prepared by combining, through high-yield condensation re...

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Published in:	Frontiers in chemistry Vol. 12; p. 1425867
Main Authors:	Finamore, Claudia, De Marino, Simona, Cassiano, Chiara, Napolitano, Giuliano, Rapacciuolo, Pasquale, Marchianò, Silvia, Biagioli, Michele, Roselli, Rosalinda, Di Giorgio, Cristina, Festa, Carmen, Fiorucci, Stefano, Zampella, Angela
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 17-07-2024
Subjects:	BAR502 bile acid receptors Chemistry fibrates hybrid prodrug metabolic profile stability cell permeation fibrates hybrid prodrug metabolic profile BAR502 stability anti-inflammatory activity bile acid receptors
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Abstract	BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we report the synthesis and the biological evaluation of a library of hybrid compounds prepared by combining, through high-yield condensation reaction, some fibrates with BAR502.The activity of the new conjugates was evaluated towards FXR, GPBAR1 and PPARα receptors, employing transactivation or cofactor recruitment assays. Compound 1 resulted as the most promising of the series and was subjected to further pharmacological investigation, together with stability evaluation and cell permeation assessment. We have proved by LCMS analysis that compound 1 is hydrolyzed in mice releasing clofibric acid and BAR505, the oxidized metabolite of BAR502, endowed with retained dual FXR/GPBAR1 activity.
AbstractList	BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we report the synthesis and the biological evaluation of a library of hybrid compounds prepared by combining, through high-yield condensation reaction, some fibrates with BAR502.The activity of the new conjugates was evaluated towards FXR, GPBAR1 and PPARα receptors, employing transactivation or cofactor recruitment assays. Compound 1 resulted as the most promising of the series and was subjected to further pharmacological investigation, together with stability evaluation and cell permeation assessment. We have proved by LCMS analysis that compound 1 is hydrolyzed in mice releasing clofibric acid and BAR505, the oxidized metabolite of BAR502, endowed with retained dual FXR/GPBAR1 activity. BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we report the synthesis and the biological evaluation of a library of hybrid compounds prepared by combining, through high-yield condensation reaction, some fibrates with BAR502.The activity of the new conjugates was evaluated towards FXR, GPBAR1 and PPARα receptors, employing transactivation or cofactor recruitment assays. Compound 1 resulted as the most promising of the series and was subjected to further pharmacological investigation, together with stability evaluation and cell permeation assessment. We have proved by LCMS analysis that compound 1 is hydrolyzed in mice releasing clofibric acid and BAR505, the oxidized metabolite of BAR502, endowed with retained dual FXR/GPBAR1 activity.BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we report the synthesis and the biological evaluation of a library of hybrid compounds prepared by combining, through high-yield condensation reaction, some fibrates with BAR502.The activity of the new conjugates was evaluated towards FXR, GPBAR1 and PPARα receptors, employing transactivation or cofactor recruitment assays. Compound 1 resulted as the most promising of the series and was subjected to further pharmacological investigation, together with stability evaluation and cell permeation assessment. We have proved by LCMS analysis that compound 1 is hydrolyzed in mice releasing clofibric acid and BAR505, the oxidized metabolite of BAR502, endowed with retained dual FXR/GPBAR1 activity.
Author	Cassiano, Chiara Festa, Carmen Fiorucci, Stefano De Marino, Simona Marchianò, Silvia Zampella, Angela Rapacciuolo, Pasquale Di Giorgio, Cristina Roselli, Rosalinda Finamore, Claudia Napolitano, Giuliano Biagioli, Michele
AuthorAffiliation	1 Department of Pharmacy , University of Naples , Naples , Italy 2 Department of Medicine and Surgery , University of Perugia , Perugia , Italy
AuthorAffiliation_xml	– name: 2 Department of Medicine and Surgery , University of Perugia , Perugia , Italy – name: 1 Department of Pharmacy , University of Naples , Naples , Italy
Author_xml	– sequence: 1 givenname: Claudia surname: Finamore fullname: Finamore, Claudia organization: Department of Pharmacy, University of Naples, Naples, Italy – sequence: 2 givenname: Simona surname: De Marino fullname: De Marino, Simona organization: Department of Pharmacy, University of Naples, Naples, Italy – sequence: 3 givenname: Chiara surname: Cassiano fullname: Cassiano, Chiara organization: Department of Pharmacy, University of Naples, Naples, Italy – sequence: 4 givenname: Giuliano surname: Napolitano fullname: Napolitano, Giuliano organization: Department of Pharmacy, University of Naples, Naples, Italy – sequence: 5 givenname: Pasquale surname: Rapacciuolo fullname: Rapacciuolo, Pasquale organization: Department of Pharmacy, University of Naples, Naples, Italy – sequence: 6 givenname: Silvia surname: Marchianò fullname: Marchianò, Silvia organization: Department of Medicine and Surgery, University of Perugia, Perugia, Italy – sequence: 7 givenname: Michele surname: Biagioli fullname: Biagioli, Michele organization: Department of Medicine and Surgery, University of Perugia, Perugia, Italy – sequence: 8 givenname: Rosalinda surname: Roselli fullname: Roselli, Rosalinda organization: Department of Medicine and Surgery, University of Perugia, Perugia, Italy – sequence: 9 givenname: Cristina surname: Di Giorgio fullname: Di Giorgio, Cristina organization: Department of Medicine and Surgery, University of Perugia, Perugia, Italy – sequence: 10 givenname: Carmen surname: Festa fullname: Festa, Carmen organization: Department of Pharmacy, University of Naples, Naples, Italy – sequence: 11 givenname: Stefano surname: Fiorucci fullname: Fiorucci, Stefano organization: Department of Medicine and Surgery, University of Perugia, Perugia, Italy – sequence: 12 givenname: Angela surname: Zampella fullname: Zampella, Angela organization: Department of Pharmacy, University of Naples, Naples, Italy
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Copyright	Copyright © 2024 Finamore, De Marino, Cassiano, Napolitano, Rapacciuolo, Marchianò, Biagioli, Roselli, Di Giorgio, Festa, Fiorucci and Zampella. Copyright © 2024 Finamore, De Marino, Cassiano, Napolitano, Rapacciuolo, Marchianò, Biagioli, Roselli, Di Giorgio, Festa, Fiorucci and Zampella. 2024 Finamore, De Marino, Cassiano, Napolitano, Rapacciuolo, Marchianò, Biagioli, Roselli, Di Giorgio, Festa, Fiorucci and Zampella
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Keywords	cell permeation fibrates hybrid prodrug metabolic profile BAR502 stability anti-inflammatory activity bile acid receptors
Language	English
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Antonio Laghezza, University of Bari Aldo Moro, Italy Edited by: Chiara Brullo, University of Genoa, Italy Reviewed by: Fabrizio Dal Piaz, University of Salerno, Italy
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Snippet	BAR502, a bile acid analogue, is active as dual FXR/GPBAR1 agonist and represents a promising lead for the treatment of cholestasis and NASH. In this paper we...
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SubjectTerms	BAR502 bile acid receptors Chemistry fibrates hybrid prodrug metabolic profile stability
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Title	BAR502/fibrate conjugates: synthesis, biological evaluation and metabolic profile
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