title: Chiral Inhibition of Rivaroxaban Derivatives Towards UDP-Glucuronosyltransferase (UGT) Isoforms.
abstract: Rivaroxaban is an oral direct factor Xa (FXa) inhibitor clinically used to prevent and treat thromboembolic disorders. Drug-drug interaction (DDI) exist for rivaroxaban and the inhibitors of CYP3A4/5. This study aims to investigate the inhibition of rivaroxaban and its derivatives with a chiral center towards UDP-glucuronosyltransferases (UGTs). Chemical synthesis was performed to obtain rivaroxaban derivatives with different chiral centers. UGTs supersomes-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was employed to evaluate the inhibition potential towards various UGT isoforms. A significant influence of rivaroxaban derivatives towards UGT1A3 was observed. Chiral centers produce different effects towards the effect of four pairs of rivaroxaban derivatives towards UGT1A3 activity, with stronger inhibition potential of S1 than R1, but stronger inhibition capability of R2, R3, R4 than S2, S3, and S4. Competitive inhibition of R3 and R4 towards UGT1A3 was demonstrated by Dixon and Lineweaver-Burk plots. In conclusion, the significant influence of rivaroxaban derivatives towards UGT1A3's activity was demonstrated in the present study. The chirality centers highly affected the inhibition behavior of rivaroxaban derivatives towards UGT1A3.
authors.affiliation: Department of Cardiology, Tianjin Union Medicine Centre, 300121, Tianjin, People's Republic of China.
authors.forename: Zhuhua
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Yong-Zhe
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery & High-Efficiency, Tianjin University, Tianjin, People's Republic of China.
authors.forename: Ai-Lun
authors.initials: AL
authors.lastname: Ma
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Wang
authors.affiliation: Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.affiliation: Tianjin Life Science Research Center, Department of Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Cui-Min
authors.initials: CM
authors.lastname: Hu
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and First Affiliated Hospital of Liaoning Medical University, Dalian, People's Republic of China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: College of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China.
authors.forename: Haina
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shandong Cancer Hospital and Institute, Shandong, People's Republic of China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Hu
authors.affiliation: School of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery & High-Efficiency, Tianjin University, Tianjin, People's Republic of China.|Collaborative Innovation Center of Chemical Science and Engineering, Tianjin University, Tianjin, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
mesh_terms: D065427:Factor Xa Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000069552:Rivaroxaban / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D065427:Factor Xa Inhibitors; D007527:Isoenzymes; D000069552:Rivaroxaban; D014453:Glucuronosyltransferase
keywords: UDP-glucuronosyltransferases (UGTs); chirality; drug-drug interaction; rivaroxaban