ABSTRACT
We studied the effects of some aniline and dioxaborininopyridine derivatives on the rate of oxidative deamination of putrescine and polyamines in a tissue with high mitotic index. These effects were evaluated quantitatively by measuring diamine oxidase and polyamine oxidase activities in a model cell-free test system of regenerating rat liver tissue. Aniline derivatives exhibited mainly antiproliferative effects and promoted oxidative degradation of putrescine, spermidine, and spermine. Dioxaborininopyridine derivatives inhibited this process, thus exhibiting carcinogenic properties.
Subject(s)
Amine Oxidase (Copper-Containing)/chemistry , Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Boron Compounds/pharmacology , Carcinogens/pharmacology , Oxidoreductases Acting on CH-NH Group Donors/chemistry , Pyridines/pharmacology , Aniline Compounds/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Boron Compounds/chemical synthesis , Carcinogens/chemical synthesis , Cell-Free System/chemistry , Cell-Free System/drug effects , Cell-Free System/metabolism , Enzyme Assays , Kinetics , Liver/chemistry , Liver/metabolism , Liver Regeneration , Male , Oxidation-Reduction , Putrescine/chemistry , Pyridines/chemical synthesis , Rats , Spermidine/chemistry , Spermine/chemistry , Structure-Activity Relationship , Polyamine OxidaseABSTRACT
In vitro immunohistochemical investigations on the human hepatoma cell line (Huh7) infected with hepatitis C virus (HCV) strain JFH-1 showed that AV0012 compound blocks the early stages of viral infection. AV0012 also blocked viral infection spread in tissue culture through the secreted virus and through tight cell-to-cell contact. AV0012 is a specific inhibitor of HCV but not of related pestivirus, flaviviruses and other RNA-containing viruses such as bovine diarrhea (BVDV), Venezuelan equine encephalitis (strain TC-83), dengue type 2 (New Guinea), yellow fever (strain 17D), west Nile fever, parainfluenza (type 3) virus, RSV (strain A2), and Rhinovirus (type 2 strain HGP). It is established that human serum does not significantly affect the antiviral activity of AV0012 in vitro. The drug combination studies with AV0012 and interferon alpha 2a in vitro showed that the two inhibitors act additively, which makes possible the use of this combination in clinical tests. AV0012 is highly soluble and stable in aqueous solutions and murine blood plasma, has limited metabolic stability, low binding to human plasma proteins, high permeability through biological membranes, and only interacts with isoenzymes 2D6 and 3A4 of human cytochrome P450. In animal pharmacokinetic studies, AV0012 was rapidly absorbed into the blood stream upon oral administration, showed sufficiently long half-elimination times, and had high oral bioavailability that reached 92% in monkeys. Further preclinical development of AV0012 is in progress.
Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/pharmacokinetics , Hepacivirus/metabolism , Hepatitis C/drug therapy , Hepatitis C/metabolism , Animals , Antiviral Agents/chemistry , Cattle , Cell Line , Drug Evaluation, Preclinical , Flavivirus/metabolism , Flavivirus Infections/drug therapy , Flavivirus Infections/metabolism , Haplorhini , Humans , Mice , RatsABSTRACT
In the framework of preclinical testing of AV0038, ethyl 2-(dimethylaminomethyl)-5-hydroxy-1-methyl-6-(pyridin-3-yl)-1H-indole-3-carboxylate, which showed high efficiency in the prevention and treatment of influenza A/Aichi/2/69 (H3N2) in mice, we have studied the drug solubility and stability in aqueous solutions, metabolic stability in human liver microsomes, stability in blood plasma of mice and humans, binding to plasma proteins of mice and humans, pharmacokinetics and bioavailability in mice, and the acute toxicity and the maximum tolerated dose. It is established that AV0038 has attractive pharmacological properties as anti-influenza drug candidate. The therapeutic doses of AV0038 do not cause acute toxicity in mice. It is expedient to continue preclinical investigations and study the drug metabolism, metabolites, and sub-chronic toxicity in test animals.
Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/pharmacokinetics , Influenza A Virus, H3N2 Subtype , Orthomyxoviridae Infections/drug therapy , Animals , Drug Evaluation, Preclinical , Humans , Male , Maximum Tolerated Dose , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/bloodABSTRACT
Pharmacological safety of a new type of HCV inhibitor, AV0012, was studied including acute, subchronic and chronic toxicity in mice, rats and monkeys. Genotoxicity was assessed using the Ames test and the chromosomal aberrations assay in the bone marrow cells of mice. It is established that AV0012 has low toxicity in SHK line mice, Wistar line rats, and monkey of Rhesus macaques species. Results obtained in the study of genetic toxicity showed that AV0012 exhibits no mutagenic activity. Data on general toxicity and mutagenicity discussed in this paper, together with data on 1 the pharmacological activity, pharmacokinetics, and metabolism published previously, allow us to consider AV0012 as a candidate drug for clinical research phase I.
