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Chiral Inhibition of Rivaroxaban Derivatives Towards UDP‐Glucuronosyltransferase (UGT) Isoforms
Author(s) -
Yao Zhuhua,
Liu YongZhe,
Ma AiLun,
Wang ShuFen,
Lu Dan,
Hu CuiMin,
Zhang YanYan,
Wang Haina,
Hu Lingyun,
Deng Jun,
Yang Kun,
Fang ZhongZe
Publication year - 2015
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.22505
Subject(s) - chemistry , rivaroxaban , glucuronidation , cyp3a4 , pharmacology , chirality (physics) , glucuronosyltransferase , drug , stereochemistry , enzyme , biochemistry , medicine , microsome , warfarin , cytochrome p450 , atrial fibrillation , nambu–jona lasinio model , chiral symmetry breaking , physics , quantum mechanics , quark
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. Chirality 27:936–943, 2015 . © 2015 Wiley Periodicals, Inc.