RESUMO
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.
Assuntos
Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Linhagem Celular , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Indicadores e Reagentes , Indinavir/síntese química , Indinavir/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , HIV/efeitos dos fármacos , Indinavir/análogos & derivados , Administração Oral , Disponibilidade Biológica , Farmacorresistência Viral , HIV/enzimologia , Protease de HIV/efeitos dos fármacos , Inibidores da Protease de HIV/administração & dosagem , Estrutura MolecularRESUMO
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.
Assuntos
Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Oxidiazóis/química , Linhagem Celular Tumoral , Farmacorresistência Viral Múltipla , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/enzimologia , HIV-1/isolamento & purificação , Humanos , Indinavir/análogos & derivados , Indinavir/síntese química , Indinavir/química , Indinavir/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Piridinas/química , EstereoisomerismoRESUMO
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.
Assuntos
Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , Indinavir/uso terapêutico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Administração Oral , Biotransformação , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Farmacorresistência Viral , Quimioterapia Combinada , Inibidores da Protease de HIV/farmacocinética , Humanos , Indinavir/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Pirróis/síntese química , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores da Protease de HIV/química , Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Animais , Cães , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/fisiologia , Inibidores da Protease de HIV/administração & dosagem , HumanosRESUMO
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.
Assuntos
Farmacorresistência Viral , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Animais , Disponibilidade Biológica , Inibidores das Enzimas do Citocromo P-450 , Cães , Inibidores da Protease de HIV/farmacocinética , HIV-1/enzimologia , Meia-Vida , Indinavir/farmacocinética , Isoenzimas/antagonistas & inibidores , Macaca mulatta , Mutação/genética , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Farmacorresistência Viral , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Animais , Disponibilidade Biológica , Linhagem Celular , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Cães , Inibidores da Protease de HIV/farmacocinética , HIV-1/enzimologia , Humanos , Técnicas In Vitro , Indinavir/farmacocinética , Indinavir/farmacologia , Macaca mulatta , Microssomos Hepáticos/metabolismo , Ratos , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologiaRESUMO
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.
Assuntos
Fármacos Anti-HIV/síntese química , Inibidores da Protease de HIV/síntese química , Aminas , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Desenho de Fármacos , Inibidores da Protease de HIV/farmacologia , Compostos Heterocíclicos , Humanos , Concentração Inibidora 50 , Mutação , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
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.
Assuntos
Adenosina/química , Citidina/análogos & derivados , Citidina/farmacologia , Hepacivirus/genética , Hepatite C/virologia , RNA Viral/genética , Adenosina/análogos & derivados , Adenosina/farmacologia , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/química , Células Cultivadas , Citidina Trifosfato/análogos & derivados , Citidina Trifosfato/química , DNA Polimerase I/antagonistas & inibidores , DNA Polimerase beta/antagonistas & inibidores , DNA Polimerase gama , DNA Polimerase Dirigida por DNA , Géis , Hepacivirus/crescimento & desenvolvimento , Humanos , Inibidores da Síntese de Ácido Nucleico , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
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.
Assuntos
Inibidores da Protease de HIV/síntese química , HIV/efeitos dos fármacos , Indinavir/análogos & derivados , Animais , Área Sob a Curva , Cães , Resistência a Medicamentos , Protease de HIV/efeitos dos fármacos , Inibidores da Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacocinética , Humanos , Indinavir/metabolismo , Indinavir/farmacocinética , Concentração Inibidora 50 , Taxa de Depuração Metabólica , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
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.
