Physicochemical properties of the nucleoside prodrug R1626 leading to high oral bioavailability

被引：28

作者：

Brandl, Michael ^{[1
]}

Wu, Xiaoyang ^{[1
]}

Holper, Marites ^{[1
]}

Hong, Lei ^{[1
]}

Jia, Zhongjiang ^{[1
]}

Birudaraj, Raj ^{[1
]}

Reddy, Micaela ^{[1
]}

Alfredson, Tom ^{[1
]}

Tran, Tony ^{[1
]}

Larrabee, Susan ^{[1
]}

Hadig, Xu ^{[1
]}

Sarma, Keshab ^{[1
]}

Washington, Carla ^{[1
]}

Hill, George ^{[1
]}

Smith, David B. ^{[1
]}

机构：

[1] Roche Palo Alto, Palo Alto, CA USA

来源：

DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY | 2008年 / 34卷 / 07期

关键词：

prodrug; nucleoside; physicochemical properties; R1626;

D O I：

10.1080/03639040701836636

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The nucleoside analog R1479 is a potent and highly selective inhibitor of NS5b-directed hepatitis C virus (HCV) RNA polymerase in vitro. Because of its limited permeability, lipophilic prodrugs of R1479 were screened. Selection of the prodrug involved optimization of solubility, permeability, and stability parameters. R1626 has dissociation constant, intrinsic solubility, log partition coefficient (n-octanol water), and Caco-2 permeability of 3.62, 0.19 mg/mL, 2.45, and 14.95 x 10(-6) cm/s, respectively. The hydrolysis of the prodrug is significantly faster in the Caco-2 experiments than in hydrolytic experiments, suggesting that the hydrolysis is catalyzed by enzymes in the cellular membrane. Using GastroPlus (TM), the physical properties of R1626 successfully predict the dose dependence of the pharmacokinetics in humans previously studied. The program predicts that if the particle size of R1626 is less than 25 mu m, it will be well absorbed. Prodrugs with a solubility of greater than 100 mu g/mL and permeability in the Caco-2 assay greater than 3 x 10(-6) cm/s are expected to achieve a high fraction absorbed.

引用

页码：683 / 691

页数：9

共 41 条

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