Chiral Inhibition of Rivaroxaban Derivatives Towards UDP-Glucuronosyltransferase (UGT) Isoforms. 2015

Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
Department of Cardiology, Tianjin Union Medicine Centre, 300121, Tianjin, People's Republic of China.

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.

UI MeSH Term Description Entries
D007527 Isoenzymes Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics. Alloenzyme,Allozyme,Isoenzyme,Isozyme,Isozymes,Alloenzymes,Allozymes
D000069552 Rivaroxaban A morpholine and thiophene derivative that functions as a FACTOR XA INHIBITOR and is used in the treatment and prevention of DEEP-VEIN THROMBOSIS and PULMONARY EMBOLISM. It is also used for the prevention of STROKE and systemic embolization in patients with non-valvular ATRIAL FIBRILLATION, and for the prevention of atherothrombotic events in patients after an ACUTE CORONARY SYNDROME. 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide,BAY 59-7939,Xarelto,BAY 59 7939,BAY 597939
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer
D014453 Glucuronosyltransferase A family of enzymes accepting a wide range of substrates, including phenols, alcohols, amines, and fatty acids. They function as drug-metabolizing enzymes that catalyze the conjugation of UDPglucuronic acid to a variety of endogenous and exogenous compounds. EC 2.4.1.17. Glucuronyltransferase,UDP Glucuronosyltransferase,17 beta-Hydroxysteroid UDP-Glucuronosyltransferase,4-Nitrophenol-UDP-Glucuronosyltransferase,7-Hydroxycoumarin UDP Glucuronyltransferase,Androsterone UDP-Glucuronosyltransferase,Bilirubin UDP-Glucuronyltransferase,Estrogen UDP-Glucuronosyltransferase,Estrone Glucuronyltransferase,Glucuronic Transferase,Morphine Glucuronyltransferase,UDP Glucuronyl Transferase,UDP-Glucuronic Acid 3-O-beta-D-Galactosyl-D-Galactose Glucuronosyltransferase,p-Nitrophenyl UDP-Glucuronosyltransferase,17 beta Hydroxysteroid UDP Glucuronosyltransferase,4 Nitrophenol UDP Glucuronosyltransferase,7 Hydroxycoumarin UDP Glucuronyltransferase,Androsterone UDP Glucuronosyltransferase,Bilirubin UDP Glucuronyltransferase,Estrogen UDP Glucuronosyltransferase,Glucuronosyltransferase, UDP,Glucuronyl Transferase, UDP,Glucuronyltransferase, 7-Hydroxycoumarin UDP,Glucuronyltransferase, Estrone,Glucuronyltransferase, Morphine,Transferase, Glucuronic,Transferase, UDP Glucuronyl,UDP Glucuronic Acid 3 O beta D Galactosyl D Galactose Glucuronosyltransferase,UDP Glucuronyltransferase, 7-Hydroxycoumarin,UDP-Glucuronosyltransferase, 17 beta-Hydroxysteroid,UDP-Glucuronosyltransferase, Androsterone,UDP-Glucuronosyltransferase, Estrogen,UDP-Glucuronosyltransferase, p-Nitrophenyl,UDP-Glucuronyltransferase, Bilirubin,p Nitrophenyl UDP Glucuronosyltransferase
D065427 Factor Xa Inhibitors Endogenous factors and drugs that inhibit or block the activity of FACTOR XA. Direct Factor Xa Inhibitor,Direct-Acting Oral Anticoagulant,Direct-Acting Oral Anticoagulants,Factor Xa Inhibitor,Direct Factor Xa Inhibitors,Anticoagulant, Direct-Acting Oral,Anticoagulants, Direct-Acting Oral,Direct Acting Oral Anticoagulant,Direct Acting Oral Anticoagulants,Inhibitor, Factor Xa,Oral Anticoagulant, Direct-Acting,Oral Anticoagulants, Direct-Acting,Xa Inhibitor, Factor

Related Publications

Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
April 2015, Die Pharmazie,
Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
August 2012, Die Pharmazie,
Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
March 2015, Chirality,
Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
July 2016, Phytotherapy research : PTR,
Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
March 2014, Phytotherapy research : PTR,
Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
September 2016, Toxicology letters,
Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
November 2016, Phytotherapy research : PTR,
Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
August 2013, Phytotherapy research : PTR,
Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
August 2012, Molecules (Basel, Switzerland),
Zhuhua Yao, and Yong-Zhe Liu, and Ai-Lun Ma, and Shu-Fen Wang, and Dan Lu, and Cui-Min Hu, and Yan-Yan Zhang, and Haina Wang, and Lingyun Hu, and Jun Deng, and Kun Yang, and Zhong-Ze Fang
December 2013, Die Pharmazie,
Copied contents to your clipboard!