RESUMO
A series of 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides was synthesized and tested for their inhibition of HIV-1 integrase catalytic activity and HIV-1 replication in cells. Structure-activity studies around lead compound 5 indicated that a coplanar relationship of metal-binding heteroatoms provides optimal binding to the integrase active site. Identification of potency-enhancing substituents and adjustments in lipophilicity provided 17b which inhibits integrase-catalyzed strand transfer with an IC(50) value of 74 nM and inhibits HIV-1 replication in cell culture in the presence of 50% normal human serum with an IC(95) value of 63 nM.
Assuntos
Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacologia , Catálise , Linhagem Celular , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , HIV-1/enzimologia , HIV-1/fisiologia , Pirazinas/síntese química , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
This Letter describes the design, synthesis, and biological evaluation of novel 3-indole sulfonamides as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) with balanced profiles against common HIV RT mutants K103N and Y181C.
Assuntos
Indóis/química , Inibidores da Transcriptase Reversa/farmacologia , Sulfonamidas/farmacologia , Cristalografia por Raios X , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/genética , Modelos Moleculares , Mutação , Inibidores da Transcriptase Reversa/química , Sulfonamidas/químicaRESUMO
A series of 10-hydroxy-7,8-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-diones was synthesized and tested for their inhibition of HIV-1 replication in cell culture. Structure-activity studies indicated that high antiviral potency against wild-type virus as well as viruses containing integrase mutations that confer resistance to three different structural classes of integrase inhibitors could be achieved by incorporation of small aliphatic groups at certain positions on the core template. An optimal compound from this study, 16, inhibits integrase strand-transfer activity with an IC(50) value of 10 nM, inhibits HIV-1 replication in cell culture with an IC(95) value of 35 nM in the presence of 50% normal human serum, and displays modest pharmacokinetic properties in rats (i.v. t(1/2)=5.3 h, F=17%).
Assuntos
Química Farmacêutica/métodos , Integrase de HIV/síntese química , Integrase de HIV/farmacologia , Integrases/genética , Mutação , Administração Oral , Animais , Antivirais/farmacologia , Disponibilidade Biológica , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Ratos , Relação Estrutura-Atividade , Replicação ViralRESUMO
A series of potent novel 8-hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 12 is active against replication of HIV-1 in cell culture with a CIC(95) of 0.31microM. Further SAR exploration led to the preparation of pseudosymmetrical tricyclic pyrrolopyrazine inhibitors 23 and 24 with further improvement in antiviral activity.
Assuntos
Inibidores de Integrase de HIV/química , Integrase de HIV , Pirazinas/química , Linhagem Celular Tumoral , Integrase de HIV/fisiologia , Inibidores de Integrase de HIV/farmacologia , Humanos , Pirazinas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia , Linfócitos T/virologiaRESUMO
Naphthyridine 7 inhibits the strand transfer of the integration process catalyzed by integrase with an IC50 of 10 nM and inhibits 95% of the spread of HIV-1 infection in cell culture at 0.39 microM. It does not exhibit cytotoxicity in cell culture at < or =12.5 microM and shows a good pharmacokinetic profile when dosed orally to rats. The antiviral activity of 7 and its effect on integration were confirmed using viruses with specific integrase mutations.
Assuntos
Fármacos Anti-HIV/síntese química , Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Naftiridinas/síntese química , Administração Oral , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Injeções Intravenosas , Naftiridinas/química , Naftiridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of potent novel dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 6 is active against replication of HIV with a CIC(95) of 0.31 microM and exhibits no shift in potency in the presence of 50% normal human serum. It displays a good pharmacokinetic profile when dosed in rats and no covalent binding with microsomal proteins in both in vitro and in vivo models.
Assuntos
Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Animais , Benzeno/química , Linhagem Celular , HIV/efeitos dos fármacos , HIV/enzimologia , HIV/fisiologia , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacocinética , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacocinética , Naftiridinas/síntese química , Administração Oral , Animais , Células Cultivadas , Integrase de HIV/efeitos dos fármacos , Integrase de HIV/genética , Inibidores de Integrase de HIV/farmacologia , Humanos , Concentração Inibidora 50 , Mutação , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 5-amino derivatives of 8-hydroxy[1,6]-naphthyridine-7-carboxamide exhibiting sub-micromolar potency against replication of HIV-1 in cell culture was identified. One of these analogs, compound 12, displayed excellent pharmacokinetic properties when dosed orally in rats and in monkeys. This compound was demonstrated to be efficacious against replication of simian-human immunodeficiency virus (SHIV) 89.6P in infected rhesus macaques.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Naftiridinas/química , Naftiridinas/farmacologia , Aminação , Inibidores de Integrase de HIV/química , Estrutura Molecular , Naftiridinas/síntese química , Relação Estrutura-AtividadeRESUMO
Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.