Metabolism study and biological evaluation of bosentan derivatives.
Bosentan, the first-in-class drug used in treatment of pulmonary arterial hypertension, is principally metabolized by the cytochromes P450, and it is responsible for cytochromes induction and drug-drug interaction events with moderate to severe consequences. A strategy to reduce drug-drug interactions consists of increasing the metabolic stability of the perpetrator, and fluorinated analogues are often designed to block the major sites of metabolism. In this paper bosentan analogues were synthesized, and their metabolism and biological activity were evaluated. All synthesized compounds showed an improved metabolic stability towards CYP2C9, with one maintaining a moderate antagonist effect towards the ETA receptor.
Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy.
Susan
S
Lepri
Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy.
Laura
L
Goracci
Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy.
Aurora
A
Valeri
Department of Chemistry, Biology and Biotechnology, University of Perugia, Via Elce di Sotto 8, 06123 Perugia, Italy. Electronic address: gabriele.cruciani@unipg.it.
Gabriele
G
Cruciani
D000818:Animals; D000077300:Bosentan; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D065729:Cytochrome P-450 CYP2C9 / Q000737:chemistry / Q000378:metabolism; D065128:Endothelin Receptor Antagonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008958:Models, Molecular; D011487:Protein Conformation; D017466:Receptors, Endothelin / Q000819:agonists / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D017466:Receptors, Endothelin; D013449:Sulfonamides; D065729:Cytochrome P-450 CYP2C9; D000077300:Bosentan
Bosentan; HLM; Metabolic specificity; Perfluorinated analogues; Phase I metabolism