RESUMO
The 2 '-deoxy-2 '-fluoro-2 '-C-methyluridine nucleotide prodrug, PSI-7851 and its single diastereomer PSI-7977 have displayed potent antiviral activity against hepatitis C virus in clinical trials, and PSI-7977 is currently in Phase III studies. As part of our SAR study of the 2 '-deoxy-2 '-fluoro-2 '- C-methyl class of nucleosides, we prepared the cyclopentyl carbocyclic uridine analog 11 and its phosphoramidate prodrug 15. Both 11 and 15 were shown not to inhibit HCV replication. This lack of activity might be attributed to the inability of the monophosphate to be converted to the corresponding diphosphate or triphosphate or the inactivity of triphosphate of 11 as an inhibitor of the polymerase.
Assuntos
Antivirais/síntese química , Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Desoxiuridina/análogos & derivados , Hepacivirus/efeitos dos fármacos , Compostos Organofosforados/síntese química , Compostos Organofosforados/farmacologia , Pró-Fármacos/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Ciclopentanos/química , Desoxiuridina/síntese química , Desoxiuridina/química , Desoxiuridina/farmacologia , Hepacivirus/enzimologia , Humanos , Compostos Organofosforados/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
In order to support bioanalytical LC/MS method development and plasma sample analysis in preclinical and clinical studies of the anti-hepatitis C-virus nucleotides, PSI-7977 and PSI-352938, the corresponding stable isotope labeled forms were prepared. These labeled compounds were prepared by addition reaction of the freshly prepared Grignard reagent (13)CD(3)MgI to the corresponding 2 '-ketone nucleosides followed by fluorination of the resulting carbinol with DAST. As expected, these 2 '-C-(trideuterated-(13)C-methyl) nucleotide prodrugs showed similar anti-HCV activity to that of the corresponding unlabeled ones.
Assuntos
Antivirais/química , Óxidos P-Cíclicos/química , Hepacivirus/efeitos dos fármacos , Nucleosídeos/química , Pró-Fármacos/química , Uridina Monofosfato/análogos & derivados , Antivirais/síntese química , Antivirais/farmacologia , Óxidos P-Cíclicos/síntese química , Óxidos P-Cíclicos/farmacologia , Halogenação , Hepatite C/tratamento farmacológico , Humanos , Marcação por Isótopo/métodos , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Sofosbuvir , Uridina Monofosfato/síntese química , Uridina Monofosfato/química , Uridina Monofosfato/farmacologiaRESUMO
Hepatitis C virus afflicts approximately 180 million people worldwide, and the development of direct acting antivirals may offer substantial benefit compared to the current standard of care. Accordingly, prodrugs of 2'-deoxy-2'-fluoro-2'-C-methylguanosine monophosphate analogues were prepared and evaluated for their anti-HCV efficacy and tolerability. These prodrugs demonstrated >1000 fold greater potency than the parent nucleoside in a cell-based replicon assay as a result of higher intracellular triphosphate levels. Further optimization led to the discovery of the clinical candidate PSI-353661, which has demonstrated strong in vitro inhibition against HCV without cytotoxicity and equipotent activity against both the wild type and the known S282T nucleoside/tide resistant replicon. PSI-353661 is currently in preclinical development for the treatment of HCV.
RESUMO
A series of novel 2'-deoxy-2'-α-fluoro-2'-ß-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs were synthesized and evaluated for their in vitro anti-HCV activity and safety. These prodrugs demonstrated a 10-100-fold greater potency than the parent nucleoside in a cell-based replicon assay due to higher cellular triphosphate levels. Our structure-activity relationship (SAR) studies provided compounds that gave high levels of active triphosphate in rat liver when administered orally to rats. These studies ultimately led to the selection of the clinical development candidate 24a (PSI-352938).