RESUMEN
A series of HIV protease inhibitors with modifications on the P3 position have been designed and synthesized. These compounds exhibit excellent antiviral activity against both the wild type enzyme and PI-resistant clinical viral isolates. The synthesis and biological activity of the compounds are described.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Línea Celular , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Indicadores y Reactivos , Indinavir/síntesis química , Indinavir/farmacología , Relación Estructura-ActividadRESUMEN
Efforts directed to identifying potent HIV protease inhibitors (PI) have yielded a class of compounds that are not only very active against wild-type (NL4-3) HIV virus but also very potent against a panel of PI-resistant viral isolates. Chemistry and biology are described.
Asunto(s)
Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , VIH/efectos de los fármacos , Indinavir/análogos & derivados , Administración Oral , Disponibilidad Biológica , Farmacorresistencia Viral , VIH/enzimología , Proteasa del VIH/efectos de los fármacos , Inhibidores de la Proteasa del VIH/administración & dosificación , Estructura MolecularRESUMEN
Replacement of the pyridylmethyl moiety in indinavir with a pyridyl oxazole yielded HIV-1 protease inhibitors (PI) with greatly improved potency against PI-resistant HIV-1 strains. A meta-methoxy group on the pyridyl ring and a gem-dimethyl methyl linkage afforded compound 10 with notable in vitro antiviral activity against HIV-1 viral strains with reduced susceptibility to the clinically available PIs. Compound 10 also demonstrated favorable in vivo pharmacokinetics in animal models.
Asunto(s)
Farmacorresistencia Viral , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Animales , Disponibilidad Biológica , Línea Celular , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Inhibidores de la Proteasa del VIH/farmacocinética , VIH-1/enzimología , Humanos , Técnicas In Vitro , Indinavir/farmacocinética , Indinavir/farmacología , Macaca mulatta , Microsomas Hepáticos/metabolismo , Ratas , Linfocitos T/efectos de los fármacos , Linfocitos T/virologíaRESUMEN
HIV-1 protease inhibitors (PI's) bearing 1,3,4-oxadiazoles at the P1' position were prepared by a novel method involving the diastereoselective installation of a carboxylic acid and conversion to the P1' heterocycle. The compounds are picomolar inhibitors of native HIV-1 protease, with most of the compounds maintaining excellent antiviral activity against a panel of PI-resistant strains.
Asunto(s)
Inhibidores de la Proteasa del VIH/química , VIH-1/efectos de los fármacos , Oxadiazoles/química , Línea Celular Tumoral , Farmacorresistencia Viral Múltiple , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/enzimología , VIH-1/aislamiento & purificación , Humanos , Indinavir/análogos & derivados , Indinavir/síntesis química , Indinavir/química , Indinavir/farmacología , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Piridinas/química , EstereoisomerismoRESUMEN
Indinavir analogues with blocked metabolism sites show highly improved pharmacokinetic profiles in animals. The cis-aminochromanol substituted analogues exhibited excellent potency against both the wild-type (NL4-3) virus and protease inhibitor-resistant HIV strains.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , VIH/efectos de los fármacos , Indinavir/análogos & derivados , Animales , Área Bajo la Curva , Perros , Resistencia a Medicamentos , Proteasa del VIH/efectos de los fármacos , Inhibidores de la Proteasa del VIH/metabolismo , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Indinavir/metabolismo , Indinavir/farmacocinética , Concentración 50 Inhibidora , Tasa de Depuración Metabólica , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is essential for the replication of viral RNA and thus constitutes a valid target for the chemotherapeutic intervention of HCV infection. In this report, we describe the identification of 2'-substituted nucleosides as inhibitors of HCV replication. The 5'-triphosphates of 2'-C-methyladenosine and 2'-O-methylcytidine are found to inhibit NS5B-catalyzed RNA synthesis in vitro, in a manner that is competitive with substrate nucleoside triphosphate. NS5B is able to incorporate either nucleotide analog into RNA as determined with gel-based incorporation assays but is impaired in its ability to extend the incorporated analog by addition of the next nucleotide. In a subgenomic replicon cell line, 2-C-methyladenosine and 2'-O-methylcytidine inhibit HCV RNA replication. The 5'-triphosphates of both nucleosides are detected intracellularly following addition of the nucleosides to the media. However, significantly higher concentrations of 2'-C-methyladenosine triphosphate than 2'-O-methylcytidine triphosphate are detected, consistent with the greater potency of 2'-C-methyladenosine in the replicon assay, despite similar inhibition of NS5B by the triphosphates in the in vitro enzyme assays. Thus, the 2'-modifications of natural substrate nucleosides transform these molecules into potent inhibitors of HCV replication.
Asunto(s)
Adenosina/química , Citidina/análogos & derivados , Citidina/farmacología , Hepacivirus/genética , Hepatitis C/virología , ARN Viral/genética , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/química , Células Cultivadas , Citidina Trifosfato/análogos & derivados , Citidina Trifosfato/química , ADN Polimerasa I/antagonistas & inhibidores , ADN Polimerasa beta/antagonistas & inhibidores , ADN Polimerasa gamma , ADN Polimerasa Dirigida por ADN , Geles , Hepacivirus/crecimiento & desarrollo , Humanos , Inhibidores de la Síntesis del Ácido Nucleico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
A series of highly potent HIV protease inhibitors have been designed and synthesized. These compounds are active against various clinical viral isolates as well as wild-type virus. The synthesis and biological activity of these HIV protease inhibitors are discussed.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Inhibidores de la Proteasa del VIH/síntesis química , Aminas , Fármacos Anti-VIH/farmacología , Línea Celular , Diseño de Fármacos , Inhibidores de la Proteasa del VIH/farmacología , Compuestos Heterocíclicos , Humanos , Concentración 50 Inhibidora , Mutación , Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
HIV-1 protease inhibitors (PI) with an N-arylpyrrole moiety in the P(3) position afforded excellent antiviral potency and substantially improved aqueous solubility over previously reported variants. The rapid in vitro clearance of these compounds in human liver microsomes prompted oral coadministration with indinavir to hinder their metabolism by the cyctochrome P450 3A4 isozyme and allow for in vivo PK assessment.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/metabolismo , VIH-1/efectos de los fármacos , Indinavir/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Administración Oral , Biotransformación , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Diseño de Fármacos , Farmacorresistencia Viral , Quimioterapia Combinada , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Indinavir/farmacología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Pirroles/síntesis química , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
A biaryl pyridylfuran P(3) substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PI's) with picomolar (IC(50)) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t(1/2) of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these compounds.
Asunto(s)
Farmacorresistencia Viral , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Animales , Disponibilidad Biológica , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Inhibidores de la Proteasa del VIH/farmacocinética , VIH-1/enzimología , Semivida , Indinavir/farmacocinética , Isoenzimas/antagonistas & inhibidores , Macaca mulatta , Mutación/genética , Relación Estructura-ActividadRESUMEN
Transposition of the pyridyl nitrogen from the P(3) substituent to the P(1)' substituent in HIV-1 protease inhibitors (PI) affords compounds such as 3 with an improved inhibitory profile against multiple P450 isoforms. These compounds also displayed increased potency, with 3 inhibiting viral spread (CIC(95)) at <8 nM for every strain of PI-resistant HIV-1 tested. The poor to modest bioavailability of these compounds may correlate in part to their aqueous solubility.
Asunto(s)
Inhibidores de la Proteasa del VIH/química , Proteasa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Animales , Perros , Farmacorresistencia Viral/efectos de los fármacos , Farmacorresistencia Viral/fisiología , Inhibidores de la Proteasa del VIH/administración & dosificación , HumanosRESUMEN
Substitution of the t-butylcarboxamide substituent in analogues of the HIV protease inhibitor (PI) Indinavir with a trifluoroethylamide moiety confers greater potency against both the wild-type (NL4-3) virus and PI-resistant HIV. The trifluoroethyl substituent also affords a slower clearance rate in vivo (dogs); however, this may be due to more potent inhibition of at least two P450 isoforms.