Design, Synthesis And Conversion Evaluation In Rats Of PSI-6130 Prodrug

Hepatitis C virus(HCV), is one of the major causes of cirrhosis, hepatocellular carcinoma. HCV infection affects 180 million people worldwide, about 3% of the world's population. A safe and effective inhibitor specific to HCV and a prophylatic vaccine against it are not yet available. Today, the standard of care for treating HCV is the combination of pegylated interferon-α(IFN-α) plus ribavirin. Unfortunately, this treatment does not show lasting improvement in 50-60% of the patients and has many disadvantages such as long treatment period, high cost and undesirable side effects.Novel treatment options now in development are focused on inhibitors of HCV specific enzymes, NS3 protease and NS5B polymerase. These agents acting in concert represent the concept of specifically targeted antiviral therapy for HCV (STAT-C). PSI-6130 (also called R-1656), chemical nameβ-D-(2'R)-2'-methyl-2'- fluorocytidine, was developed through a partnership formed by Roche and Pharmasset to synthesize nucleoside polymerase NS5B inhibitors for HCV treatment. The compound potently inhibited HCV replication in subgenomic HCV replicon cells (EC90 = 4.6μM). Pharmacokinetic studies in rhesus monkeys, however, revealed slow and incomplete absorption and an oral bioavailability of 24.0%. To improve absorption and drug exposure and to limit or eliminate the formation of the uridine metabolite led to the identification of PSI-6130 prodrug, R-7128. R-7128 is ongoing a phase IIb study.In this study, based on the literature, we selected the PSI-6130 as the original drug.The reasons for the low bioavailability may be that two hydroxyl groups and one amino group of PSI-6130 make it difficult through the biofilm. And its amino is unstable under acidic conditions. Therefore, moderately decreasing the polarity of the original drug and increasing its stability of the compound should be considered. Consulting some successful prodrug design strateg, such as the prodrug of acyclovir(ACV), valaciclovir(VACV), and the prodrug of ganciclovir(GCV), valganciclovir (VGCV), to improve the drug metabolic activity of PSI-6130, seven PSI-6130 prodrugs were designed. Five new PSI-6130 prodrugs (Ⅰ,Ⅲ,Ⅳ,Ⅴ,Ⅶ) were designed and synthesized in this research. The structures of these target compounds were identified by 13C-NMR, MS and 1H-NMR. The purity of these compounds was determined by HPLC. Synthetic routes of the target compounds were investigated and optimized.The conversion efficiency of these new PSI-6130 prodrugs was evaluated by oral bioavailability test in rats. The concentration of PSI-6130 in rat plasma was detected after PSI-6130 i.v. administration (2mg/ml/kg,0.00772mmol/ml/kg) and PSI-6130, prodrugs p.o. administration (0.019 mmol/2.5ml/kg, N=3) respectively. The results show that the oral bioavailability of these five prodrugs had greatly improvement against PSI-6130. The conversion efficiencies of prodrugsⅠ,Ⅴ,Ⅲ,ⅣandⅦwere 129%, 88%, 77.8%, 63.7% and 58.1% respectively.The following conclusions are obtained through this research: 1) It is a suitable strategy for designing PSI-6130 prodrugs that 4-NH2 or/and 3'-OH, 5'-OH are acylated or/and esterified with the valine. 2) Prodrug formed by 4-NH2 of PSI-6130 monoacylated with valine has better oral bioavailability than those formed by 4-NH2 or/and 3'-OH, 5'-OH acylated or/and esterified with valine. The measured octanol-water partition coefficient (LogP value) of compound I maybe the reason of good oral bioavailability.