ABSTRACT
Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Virus Replication/drug effects , Animals , Antiviral Agents/pharmacokinetics , Dogs , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Pyrimidines/pharmacokinetics , Rats , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Thiazoles/pharmacologyABSTRACT
Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.
Subject(s)
Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , Furans/chemistry , Hepacivirus/enzymology , Pyrimidine Nucleosides/chemistry , Pyrimidines/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Benzofurans/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Furans/chemical synthesis , Furans/pharmacokinetics , Half-Life , Liver/metabolism , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacokinetics , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , RNA-Dependent RNA Polymerase/metabolism , Rats , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.
Subject(s)
Antiviral Agents/chemistry , Benzothiazoles/chemistry , Hepacivirus/drug effects , Pyrimidines/chemistry , Virus Replication/drug effects , Animals , Dogs , Haplorhini , Hepacivirus/physiology , Methylation , Rodentia , Species SpecificityABSTRACT
Compound 1 was identified as a HCV replication inhibitor from screening/early SAR triage. Potency improvement was achieved via modulation of substituent on the 5-azo linkage. Due to potential toxicological concern, the 5-azo linkage was replaced with 5-alkenyl or 5-alkynyl moiety. Analogs containing the 5-alkynyl linkage were found to be potent inhibitors of HCV replication. Further evaluation identified compounds 53 and 63 with good overall profile, in terms of replicon potency, selectivity and in vivo characteristics. Initial target engagement studies suggest that these novel carbanucleoside-like derivatives may inhibit the HCV replication complex (replicase).
Subject(s)
Hepacivirus/drug effects , Hepatitis C/drug therapy , Pyrimidines/pharmacology , Virus Replication/drug effects , Animals , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
As part of an ongoing program to develop novel antitumor agents over the years, we have synthesized and evaluated a number of 4'-C-substituted nucleosides. A few years ago, we reported the first synthesis of 4'-C-hydroxymethyl-2'-fluoro arabino nucleosides, which did not exhibit any cytotoxicity. In our exploration of related compounds, we synthesized and evaluated the 4'-C-methyl-2'-fluoro arabino nucleosides in both the purine and pyrimidine series. In the pyrimidine series, 1-(4-C-methyl-2-fluoro-beta-D-arabinofuranosyl) cytosine (13) was found to be highly cytotoxic and had significant antitumor activity in mice implanted with human tumor xenografts. The synthesis and anticancer activity of this series of nucleosides are reported.
Subject(s)
Antineoplastic Agents/therapeutic use , Arabinonucleosides/therapeutic use , Neoplasms/drug therapy , Pyrimidine Nucleosides/therapeutic use , Pyrimidine Nucleotides/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Arabinonucleosides/chemical synthesis , Arabinonucleosides/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Halogenation , Humans , Mice , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleotides/chemical synthesis , Pyrimidine Nucleotides/chemistryABSTRACT
Our studies have led to the identification of an E. coli PNP mutant (M64V) that is able to cleave numerous 5'-modified nucleoside analogs with much greater efficiency than the wild-type enzyme. The biological activity of the three best substrates of this mutant (9-[6-deoxy-alpha-L-talofuranosyl]-6-methylpurine (methyl(talo)-MeP-R), 9-[6-deoxy-alpha-L-talofuranosyl]-2-F-adenine, and 9-[alpha-L-lyxofuranosyl]-2-F-adenine) were evaluated so that we can optimally utilize these compounds. Our results indicated that the mechanism of toxicity of methyl(talo)-MeP-R to mice was due to its cleavage to MeP by a bacterial enzyme, and that the toxicity of the two F-Ade analogs was due to their cleavage to F-Ade by mammalian methylthioadenosine phosphorylase.
