ABSTRACT
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%).
Subject(s)
Chemistry, Pharmaceutical/methods , HIV Integrase/chemical synthesis , HIV Integrase/pharmacology , Integrases/genetics , Mutation , Administration, Oral , Animals , Antiviral Agents/pharmacology , Biological Availability , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Rats , Structure-Activity Relationship , Virus ReplicationABSTRACT
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.
Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase , Pyrazines/chemistry , Cell Line, Tumor , HIV Integrase/physiology , HIV Integrase Inhibitors/pharmacology , Humans , Pyrazines/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes/enzymology , T-Lymphocytes/virologyABSTRACT
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.
Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Animals , Benzene/chemistry , Cell Line , HIV/drug effects , HIV/enzymology , HIV/physiology , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacokinetics , Humans , Microsomes, Liver/drug effects , Models, Molecular , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
The increasing incidence of resistance to current HIV-1 therapy underscores the need to develop antiretroviral agents with new mechanisms of action. Integrase, one of three viral enzymes essential for HIV-1 replication, presents an important yet unexploited opportunity for drug development. We describe here the identification and characterization of L-870,810, a small-molecule inhibitor of HIV-1 integrase with potent antiviral activity in cell culture and good pharmacokinetic properties. L-870,810 is an inhibitor with an 8-hydroxy-(1,6)-naphthyridine-7-carboxamide pharmacophore. The compound inhibits HIV-1 integrase-mediated strand transfer, and its antiviral activity in vitro is a direct consequence of this ascribed effect on integration. L-870,810 is mechanistically identical to previously described inhibitors from the diketo acid series; however, viruses selected for resistance to L-870,810 contain mutations (integrase residues 72, 121, and 125) that uniquely confer resistance to the naphthyridine. Conversely, mutations associated with resistance to the diketo acid do not engender naphthyridine resistance. Importantly, the mutations associated with resistance to each of these inhibitors map to distinct regions within the integrase active site. Therefore, we propose a model of the two inhibitors that is consistent with this observation and suggests specific interactions with discrete binding sites for each ligand. These studies provide a structural basis and rationale for developing integrase inhibitors with the potential for unique and nonoverlapping resistance profiles.
Subject(s)
HIV Infections/drug therapy , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Naphthyridines/pharmacology , Animals , Cells, Cultured , Dogs , Drug Resistance, Multiple , Drug Resistance, Viral , HIV Integrase/genetics , HIV Integrase/metabolism , HIV Integrase Inhibitors/chemistry , HIV-1/enzymology , HIV-1/genetics , HIV-2/drug effects , Humans , Macaca mulatta , Male , Mutagenesis, Site-Directed , Naphthyridines/chemistry , Rats , Simian Immunodeficiency Virus/drug effects , T-Lymphocytes/cytology , T-Lymphocytes/virology , Virus Integration/drug effectsABSTRACT
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.
