ABSTRACT
During a random screening of representative libraries of nucleoside analogues we discovered that the adenine derivatives FEVB28 and FEG118 were Flaviviridae inhibitors endowed with potency comparable, if not superior, to that of ribavirin. Those studies prompted us to design a new class of protected nucleoside analogs, reported herein, which displays interesting anti-bovine viral diarrhea virus (BVDV) activity and low cytotoxicity in cell-based assays (4, 23, 29 EC(50): 14, 11, 26 microM respectively, CC(50)>100 microM) and appreciable activity in enzyme assays against the RNA dependent RNA polymerase (RdRp) of BVDV (4, 23, 29, RdRp inhibition activity 27, 16, 15 microM respectively). A molecular modeling study was also carried out to highlight the possible interactions between this compounds class and the corresponding hepatitis C virus (HCV) enzyme.
Subject(s)
Adenine Nucleotides/chemical synthesis , Adenine Nucleotides/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Flaviviridae/drug effects , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , CD4-Positive T-Lymphocytes/drug effects , Cattle , Cell Line , Chromatography, Thin Layer , Computer Simulation , Cricetinae , Diarrhea Viruses, Bovine Viral/drug effects , Drug Design , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Entropy , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Structure-Activity Relationship , Tetrazolium Salts , ThiazolesABSTRACT
GW196771 is a potent antagonist of the modulatory glycine site of the N-methyl-D-aspartate (NMDA) receptor exhibiting outstanding in vivo profile in different animal models of chronic pain. With the aim to maximize the drug delivery to the target organs a suitable "pro-drug approach" was attempted; in this regards two conjugates of GW196771 with nutrients actively transported into the brain, namely adenosine and glucose, were prepared and investigated. These compounds, were evaluated in vitro in terms of their stability in rat plasma and in vivo on rats. Although an improvement was observed in terms of brain penetration of the esters vs. the parent compound, the amount of the latter did not increase significantly, probably due to some degradation events in the brain, different from the expected ester hydrolysis, resulting in a reduced availability of GW196771.