RESUMO
A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.
Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos/química , Nucleosídeos/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Amidas/química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Antivirais/farmacocinética , Células CACO-2 , Linhagem Celular , Cricetinae , Descoberta de Drogas , Farmacorresistência Viral , Halogenação , Hepacivirus/genética , Hepacivirus/fisiologia , Hepatite C/tratamento farmacológico , Humanos , Metilação , Simulação de Acoplamento Molecular , Nucleosídeos/farmacocinética , Ácidos Fosfóricos/química , Ácidos Fosfóricos/farmacocinética , Ácidos Fosfóricos/farmacologia , Mutação Puntual , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Ribose modified 1'-C-cyano pyrimidine nucleosides were synthesized. A silver triflate mediated Vorbrüggen reaction was used to generate the nucleoside scaffold and follow-up chemistry provided specific ribose modified analogs. Nucleosides and phosphoramidate prodrugs were tested for their anti-HCV activity.
Assuntos
RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hepacivirus/enzimologia , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/farmacologia , Técnicas de Química Sintética , Inibidores Enzimáticos/química , Nucleosídeos de Pirimidina/químicaRESUMO
The first synthesis of 1'-C-CN, 2'-F, 2'-C-Me pyrimidines is described. Anti-HCV activity was assessed and compared to the 1'-C-CN, 2'-C-Me as well as the 2'-F, 2'-C-Me pyrimidines. A phosphoramidate prodrug of the cytidine derivative showed activity in the low micromolar range against HCV replicons.
Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/farmacologia , Amidas/química , Amidas/farmacologia , Linhagem Celular , Halogenação , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Metilação , Ácidos Fosfóricos/química , Ácidos Fosfóricos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Replicon/efeitos dos fármacosRESUMO
A sulfonamide replacement of the P2-P3 amide bond in the context of macrocyclic HCV NS3 protease inhibitors was investigated. These analogs displayed good inhibitory potency in the absence of any P3 capping group. The synthesis and preliminary SAR are described.
Assuntos
Hepacivirus/efeitos dos fármacos , Sulfonamidas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
HIV-1 RNase H breaks down the intermediate RNA-DNA hybrids during reverse transcription, requiring two divalent metal ions for activity. Pyrimidinol carboxylic acid and N-hydroxy quinazolinedione inhibitors were designed to coordinate the two metal ions in the active site of RNase H. High-resolution (1.4 Å to 2.1 Å) crystal structures were determined with the isolated RNase H domain and reverse transcriptase (RT), which permit accurate assessment of the metal and water environment at the active site. The geometry of the metal coordination suggests that the inhibitors mimic a substrate state prior to phosphodiester catalysis. Surface plasmon resonance studies confirm metal-dependent binding to RNase H and demonstrate that the inhibitors do not bind at the polymerase active site of RT. Additional evaluation of the RNase H site reveals an open protein surface with few additional interactions to optimize active-site inhibitors.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Quinazolinonas/farmacologia , Ribonuclease H/antagonistas & inibidores , Sequência de Aminoácidos , Cristalização , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/química , HIV-1/enzimologia , Conformação Molecular , Dados de Sequência Molecular , Pirimidinas/química , Quinazolinonas/química , Ribonuclease H/química , Relação Estrutura-AtividadeRESUMO
Pyrimidinol carboxylic acids were designed as inhibitors of HIV-1 RNase H function. These molecules can coordinate to two divalent metal ions in the RNase H active site. Inhibition of enzymatic activity was measured in a biochemical assay, but no antiviral effect was observed. Binding was demonstrated via a solid state structure of the isolated p15-Ec domain of HIV-1 RT showing inhibitor and two Mn(II) ions bound to the RNase H active site.
Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Pirimidinas/farmacologia , Ribonuclease H/antagonistas & inibidores , Ácidos Carboxílicos , Domínio Catalítico , Desenho de Fármacos , Humanos , Ligação Proteica , Pirimidinas/químicaRESUMO
A series of 3,4,5-trisubstituted 1,2,4-4H triazole derivatives was synthesized and investigated for HIV-1 reverse transcriptase inhibition. An X-ray structure with HIV-1 RT secured the binding mode and allowed the key interactions with the enzyme to be identified.