In vitro evaluation of 9-(2-phosphonylmethoxyethyl)adenine ester analogues, a series of anti-HBV structures with improved plasma stability and liver release

Archives of Pharmacal Research
Sha LiaoJian-Wei Xie

Abstract

Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis and hepatocellular carcinoma, but few drugs are available for its treatment. Acyclic nucleoside phosphonates (ANPs) have remarkable antivirus activities but are not easily absorbed from the gastrointestinal tract and accumulate in the kidneys, resulting in nephrotoxicity. Therefore, there is a need to find effective liver site-specific prodrugs. The dipivaloyloxymethyl ester of 9-(2-phosphonylmethoxyethyl)adenine (PMEA)-adefovir dipivoxil (ADV)-is a first-line therapy drug for chronic hepatitis B with a low therapeutic index because of renal toxicity and low hepatic uptake. In this study, a series of PMEA derivatives were synthesized to enhance plasma stability and liver release. The metabolic stability of ADV (Chemical I) and its two analogues (Chemicals II and III) was evaluated in rat plasma and liver homogenate in vitro. An ion-pair reverse-phase HPLC-UV method and a hybrid ion trap and high-resolution time-of-flight mass spectrometry (LC-IT-TOF-MS) were used to evaluate the degradation rate of the analogues and to identify their intermediate metabolites, respectively. Chemicals I and II were hydrolyzed by cleavage of the C-O bond to give monoesters. Suff...Continue Reading

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Citations

Oct 27, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Iwona E GłowackaDorota G Piotrowska
Jul 5, 2018·Natural Product Research·Cai-Ping YaoGui-Shan Tan
Aug 31, 2019·Future Medicinal Chemistry·Kenneth M Heidel, Cynthia S Dowd

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