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
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
GS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, including in vitro antiviral activity, selectivity, cross-resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC50s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC50 = 316 nM). Additive to synergistic in vitro antiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS-9451 levels were â¼40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results of in vitro cross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Inibidores de Proteases/farmacologia , Quinolinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Benzimidazóis/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Sinergismo Farmacológico , Quimioterapia Combinada , Fluorenos/farmacologia , Haplorrinos , Hepacivirus/fisiologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Humanos , Concentração Inibidora 50 , Interferon-alfa/farmacologia , Inibidores de Proteases/farmacocinética , Purinas/farmacologia , Piridazinas/farmacologia , Quinolinas/farmacocinética , Ratos , Replicon/efeitos dos fármacos , Ribavirina/farmacologia , Proteínas não Estruturais Virais/metabolismoRESUMO
The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with l-alanine-isopropyl ester and phenol moieties attached to the 5'-phosphate that release the nucleoside monophosphate in hepatocytes and a 3'-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equivalent surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be critical to the effectiveness of GS-6620 in nonclinical species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concentration. Higher rates of metabolism were observed at lower concentrations that were unable to saturate intestinal efflux transporters. In first-in-human clinical trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3'-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metabolism and relatively poor oral absorption in humans.
Assuntos
Antivirais/farmacocinética , Pró-Fármacos/farmacocinética , Administração Oral , Animais , Antivirais/farmacologia , Células CACO-2 , Linhagem Celular , Cricetinae , Cães , Hepacivirus/efeitos dos fármacos , Humanos , Macaca fascicularis , Masculino , Mesocricetus , Pró-Fármacos/farmacologiaRESUMO
As a class, nucleotide inhibitors (NIs) of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase offer advantages over other direct-acting antivirals, including properties, such as pangenotype activity, a high barrier to resistance, and reduced potential for drug-drug interactions. We studied the in vitro pharmacology of a novel C-nucleoside adenosine analog monophosphate prodrug, GS-6620. It was found to be a potent and selective HCV inhibitor against HCV replicons of genotypes 1 to 6 and against an infectious genotype 2a virus (50% effective concentration [EC50], 0.048 to 0.68 µM). GS-6620 showed limited activities against other viruses, maintaining only some of its activity against the closely related bovine viral diarrhea virus (EC50, 1.5 µM). The active 5'-triphosphate metabolite of GS-6620 is a chain terminator of viral RNA synthesis and a competitive inhibitor of NS5B-catalyzed ATP incorporation, with Ki/Km values of 0.23 and 0.18 for HCV NS5B genotypes 1b and 2a, respectively. With its unique dual substitutions of 1'-CN and 2'-C-Me on the ribose ring, the active triphosphate metabolite was found to have enhanced selectivity for the HCV NS5B polymerase over host RNA polymerases. GS-6620 demonstrated a high barrier to resistance in vitro. Prolonged passaging resulted in the selection of the S282T mutation in NS5B that was found to be resistant in both cellular and enzymatic assays (>30-fold). Consistent with its in vitro profile, GS-6620 exhibited the potential for potent anti-HCV activity in a proof-of-concept clinical trial, but its utility was limited by the requirement of high dose levels and pharmacokinetic and pharmacodynamic variability.
Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos/química , Nucleosídeos/farmacologia , Pró-Fármacos/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/efeitos adversos , Linhagem Celular Tumoral , Sobrevivência Celular , Células Hep G2 , Humanos , Nucleosídeos/efeitos adversos , Pró-Fármacos/efeitos adversos , Pró-Fármacos/química , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
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
The first synthesis of 1'-cyano-2'-C-methyl pyrimidine nucleosides is described. Anti-HCV activity of these nucleosides and their nucleotide phosphoramidate prodrugs was assessed and compared to the 1'-unsubstituted counterparts and to the related 1'-cyano-2'-C-methyl C-nucleoside parent of GS-6620.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Nucleosídeos/farmacologia , Nucleosídeos de Pirimidina/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/química , RNA Polimerase Dependente de RNA/metabolismo , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
A novel, potent, and orally bioavailable class of product-like inhibitors of the HCV NS3 protease was discovered by constraining the P2-P3 amide bond and the P3 hydrocarbon substituent to the protease-bound conformation. This preorganization was accomplished by incorporation of the P2-P3 amide into a six-membered ring attached to the P2-proline 5-position. Isothermal calorimetric characterization of the role of hydrocarbon substitution of this six-membered ring, upon binding the HCV NS3 protease, was found to be exclusively entropic in nature. The synthesis, preliminary SAR and pharmacokinetic profiling of this compact, indolizidinone-derived scaffold are described.
Assuntos
Inibidores Enzimáticos/farmacologia , Indolizinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Indolizinas/administração & dosagem , Indolizinas/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
A series of 1'-substituted analogs of 4-aza-7,9-dideazaadenosine C-nucleoside were prepared and evaluated for the potential as antiviral agents. These compounds showed a broad range of inhibitory activity against various RNA viruses. In particular, the whole cell potency against HCV when R=CN was attributed to inhibition of HCV NS5B polymerase and intracellular concentration of the corresponding nucleoside triphosphate.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Antivirais/química , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Humanos , Estrutura Molecular , Nucleosídeos/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/efeitos dos fármacosRESUMO
A series of 2'-C-methyl branched purine and pyrimidine C-nucleosides were prepared. Their anti-HCV activity and pharmacological properties were profiled, and compared with known 2'-C-Me N-nucleoside counterparts. In particular, 2'-C-Me 4-aza-7,9-dideazaadenosine C-nucleoside (2) was found to have potent and selective anti-HCV activity in vitro as well as a favorable pharmacokinetic profile and in vivo potential for enhanced potency over the corresponding N-nucleoside.
Assuntos
Antivirais/síntese química , Compostos Aza/síntese química , Hepacivirus/efeitos dos fármacos , Nucleosídeos de Purina/síntese química , Nucleosídeos de Pirimidina/síntese química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Linhagem Celular , Cricetinae , Cães , Hepacivirus/enzimologia , Hepacivirus/crescimento & desenvolvimento , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Humanos , Injeções Intravenosas , Cultura Primária de Células , Nucleosídeos de Purina/farmacocinética , Nucleosídeos de Purina/farmacologia , Nucleosídeos de Pirimidina/farmacocinética , Nucleosídeos de Pirimidina/farmacologia , RNA Polimerase Dependente de RNA/metabolismo , Ratos , Proteínas não Estruturais Virais/metabolismoRESUMO
A potent and novel class of phosphinic acid derived product-like inhibitors of the HCV NS3/4A protease was discovered previously. Modification of the phosphinic acid and quinoline heterocycle led to GS-9256 with potent cell-based activity and favorable pharmacokinetic parameters. Based on these attributes, GS-9256 was advanced to human clinical trial as a treatment for chronic infection with genotype 1 HCV.
Assuntos
Proteínas de Transporte/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Peptídeos Cíclicos/química , Ácidos Fosfínicos/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Cães , Inibidores Enzimáticos/síntese química , Hepacivirus/enzimologia , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Ácidos Fosfínicos/síntese química , Ácidos Fosfínicos/farmacologia , SuínosRESUMO
The discovery of GS-9451 is reported. Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats, dogs and monkeys.
Assuntos
Antivirais/síntese química , Ácidos Carboxílicos/síntese química , Hepacivirus/efeitos dos fármacos , Quinolinas/síntese química , Inibidores de Serina Proteinase/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Disponibilidade Biológica , Células CACO-2 , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/farmacologia , Cristalografia por Raios X , Cães , Hepacivirus/química , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Macaca fascicularis , Modelos Moleculares , Quinolinas/farmacocinética , Quinolinas/farmacologia , Ratos , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/químicaRESUMO
There is an urgent need for the development of novel antimicrobial agents that offer effective treatment against MRSA. Using a new class of dipeptide antibiotic TAN-1057A/B as lead, we designed, synthesized and evaluated analogs of TAN-1057A/B. Several novel dihydropyrimidinone antibiotics demonstrating comparable antibiotic efficacy while possessing favorable selectivity were identified.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
A potent and novel class of product-like inhibitors of the HCV NS3 protease was discovered by employing a phosphinic acid as a carboxylate isostere. The replicon activity and pharmacokinetic profile of this series of compounds was optimized by exploring the substitution of the phosphinic acid, as well as conformationally constraining these compounds through macrocyclization. The syntheses and preliminary biological evaluation of these phosphinic acids is described.
Assuntos
Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Ácidos Fosfínicos/síntese química , Ácidos Fosfínicos/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Ciclização , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ácidos Fosfínicos/químicaRESUMO
A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Compostos Heterocíclicos/química , Pirimidinonas/química , Inibidores da Transcriptase Reversa/química , Timina/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Cães , Transcriptase Reversa do HIV/metabolismo , Humanos , Ligação de Hidrogênio , Microssomos/metabolismo , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/metabolismo , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacocinética , Relação Estrutura-Atividade , Timina/síntese química , Timina/química , Timina/farmacocinéticaRESUMO
A series of N1-alkyl pyrimidinediones were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our efforts identified compound 10b, which represents the lead compound in this series with pharmacokinetics and antiviral potency that may support once-daily dosing.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/química , Pirimidinonas/química , Inibidores da Transcriptase Reversa/química , Timina/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Cães , Transcriptase Reversa do HIV/metabolismo , Humanos , Microssomos/metabolismo , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacocinética , Relação Estrutura-Atividade , Timina/síntese química , Timina/química , Timina/farmacocinéticaRESUMO
GS-9160 is a novel and potent inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN) that specifically targets the process of strand transfer. It is an authentic inhibitor of HIV-1 integration, since treatment of infected cells results in an elevation of two-long terminal repeat circles and a decrease of integration junctions. GS-9160 has potent and selective antiviral activity in primary human T lymphocytes producing a 50% effective concentration (EC(50)) of approximately 2 nM, with a selectivity index (50% cytotoxic concentration/EC(50)) of approximately 2,000. The antiviral potency of GS-9160 decreased by 6- to 10-fold in the presence of human serum. The antiviral activity of GS-9160 is synergistic in combination with representatives from three different classes of antiviral drugs, namely HIV-1 protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors. Viral resistance selections performed with GS-9160 yielded a novel pattern of mutations within the catalytic core domain of IN; E92V emerged initially, followed by L74M. While E92V as a single mutant conferred 12-fold resistance against GS-9160, L74M had no effect as a single mutant. Together, these mutations conferred 67-fold resistance to GS-9160, indicating that L74M may potentiate the resistance caused by E92V. The pharmacokinetic profile of GS-9160 in healthy human volunteers revealed that once-daily dosing was not likely to achieve antiviral efficacy; hence, the clinical development of this compound was discontinued.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Domínio Catalítico/genética , Linhagem Celular , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Viral , Sinergismo Farmacológico , Integrase de HIV/genética , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacocinética , Inibidores da Protease de HIV/farmacologia , HIV-1/enzimologia , HIV-1/genética , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Mutação , Estrutura Terciária de Proteína , Proteínas Recombinantes/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Sensibilidade e EspecificidadeRESUMO
A series of C3 halobenzyl-substituted tricyclic HIV integrase inhibitors was prepared. Improvement in cell-based inhibitor potency was observed in comparison to previously disclosed tricyclic pyrroloquinolines carrying the 'halobenzyl tail' at the lactam nitrogen. Animal PK for several of the C3-substituted inhibitors was examined, with a dihaloaryl analog achieving good balance in protein-shifted EC(50) and t(1/2) in animal PK studies.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Administração Oral , Animais , Fármacos Anti-HIV/química , Cães , Desenho de Fármacos , Inibidores de Integrase de HIV/química , Humanos , Estrutura Molecular , Pirróis/química , Quinolinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
SAR studies on the para-fluorobenzyl moiety of tricyclic HIV integrase inhibitors are discussed and lead compounds with potency and PK properties comparable to raltegravir were identified.
Assuntos
Fluorbenzenos/química , Inibidores de Integrase de HIV/síntese química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Ligação Competitiva/fisiologia , Disponibilidade Biológica , Linhagem Celular , Cães , Fluorbenzenos/metabolismo , Fluorbenzenos/farmacologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/metabolismo , Humanos , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A novel class of phosphonate derivatives was designed to mimic the interaction of product-like carboxylate based inhibitors of HCV NS3 protease. A phosphonic acid (compound 2) was demonstrated to be a potent HCV NS3 protease inhibitor, and a potential candidate for treating HCV infection. The syntheses and preliminary biological evaluation of this phosphonate class of inhibitor are described.