RESUMO
A series of N1 acetamide substituted naphthyridinone HIV-1 integrase inhibitors have been explored to understand structure-activity relationships (SAR) with various C3 amide groups. Investigations were evaluated using integrase enzyme inhibition, antiviral activity and protein binding effects to optimize the sub-structures. Lipophilicity was also incorporated to understand ligand lipophilic efficiency as a function of the structural modifications. Three representative analogs were further examined in a peripheral blood mononuclear cell (PBMC) antiviral assay as well as in vitro and in vivo drug metabolism and pharmacokinetic studies.
Assuntos
Acetamidas/química , Amidas/química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , Naftiridinas/farmacologia , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Estrutura Molecular , Naftiridinas/síntese química , Naftiridinas/química , Relação Estrutura-AtividadeRESUMO
A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.
Assuntos
Antivirais/farmacologia , Ácidos Borônicos/química , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Antivirais/química , Descoberta de Drogas , Farmacorresistência Viral/genética , Hepacivirus/enzimologia , Hepacivirus/genética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.
Assuntos
Inibidores de Integrase de HIV/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Piridonas/síntese química , Animais , Cães , Células HeLa , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Macaca fascicularis , Masculino , Oxazinas , Piperazinas , Piridonas/química , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Several highly deuterated analogs of the HIV-1 protease inhibitor brecanavir have been prepared to study the effect of deuterium upon metabolic stability. The sites for deuterium incorporation were initially chosen to maximize the potential for a kinetic isotope effect; locations where C-H bond breaking is the rate limiting step. The analogs have been profiled in both in vitro and in vivo pharmacokinetic studies and the result will be described herein.
Assuntos
Benzodioxóis/síntese química , Carbamatos/síntese química , Inibidores da Protease de HIV/síntese química , Administração Intravenosa , Animais , Área Sob a Curva , Benzodioxóis/química , Benzodioxóis/farmacocinética , Carbamatos/química , Carbamatos/farmacocinética , Deutério/química , Deutério/farmacocinética , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacocinética , Hepatócitos/metabolismo , Humanos , Taxa de Depuração Metabólica , Modelos Químicos , Estrutura Molecular , RatosRESUMO
This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoyl pyridone analogues to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nanomolar potency in standard antiviral assays. An additional hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clinically relevant resistant viruses. These findings led to additional cyclic tethering of the naked hydroxyl group resulting in tricyclic carbamoyl pyridone inhibitors to address remaining issues and deliver potential clinical candidates. The tricyclic carbamoyl pyridone derivatives described herein served as the immediate leads in molecules to the next generation integrase inhibitor dolutegravir which is currently in late stage clinical evaluation.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/efeitos dos fármacos , Piridonas/farmacologia , Animais , Cromatografia Líquida , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacocinética , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Piridonas/química , Piridonas/farmacocinética , RatosRESUMO
Substituent effects of a series of N1 protio and methyl naphthyridinone HIV-1 integrase strand-transfer inhibitors has been explored. The effects of combinations of the N1 substituent and C3 amide groups was extensively studied to compare enzyme inhibition, antiviral activity and protein binding effects on potency. The impact of substitution on ligand efficiency was considered and several compounds were advanced into in vivo pharmacokinetic studies ultimately leading to the clinical candidate GSK364735.
Assuntos
Amidas/química , Naftiridinas/química , Bioensaio , Ativação Enzimática/efeitos dos fármacos , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Naftiridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of naphthyridinone HIV-1 integrase strand-transfer inhibitors have been designed based on a psdeudo-C2 symmetry element present in the two-metal chelation pharmacophore. A combination of two distinct inhibitor binding modes resulted in potent inhibition of the integrase strand-transfer reaction in the low nM range. Effects of aryl and N1 substitutions are disclosed including the impact on protein binding adjusted antiviral activity.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Naftiridinas/farmacologia , HIV-1 , Naftiridinas/químicaRESUMO
Synthesis of several pyrazolo[1,5-c]pyrimidines, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines with potent activity against herpes simplex viruses is described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity similar or better than acyclovir are described.
Assuntos
Antivirais/química , Herpesviridae/efeitos dos fármacos , Pirimidinas/química , Triazinas/química , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Chlorocebus aethiops , Infecções por Herpesviridae/tratamento farmacológico , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Triazinas/síntese química , Triazinas/farmacocinética , Células VeroRESUMO
Clinical trials of the first approved integrase inhibitor (INI), raltegravir, have demonstrated a drop in the human immunodeficiency virus type 1 (HIV-1) RNA loads of infected patients that was unexpectedly more rapid than that with a potent reverse transcriptase inhibitor, and apparently dose independent. These clinical outcomes are not understood. In tissue culture, although their inhibition of integration is well documented, the effects of INIs on levels of unintegrated HIV-1 cDNAs have been variable. Furthermore, there has been no report to date on an INI's effect on these episomal species in vivo. Here, we show that prophylactic treatment of transgenic rats with the strand transfer INI GSK501015 reduced levels of viral integrants in the spleen by up to 99.7%. Episomal two-long-terminal-repeat (LTR) circles accumulated up to sevenfold in this secondary lymphoid organ, and this inversely correlated with the impact on the proviral burden. Contrasting raltegravir's dose-ranging study with HIV patients, titration of GSK501015 in HIV-infected animals demonstrated dependence of the INI's antiviral effect on its serum concentration. Furthermore, the in vivo 50% effective concentration calculated from these data best matched GSK501015's in vitro potency when serum protein binding was accounted for. Collectively, this study demonstrates a titratable, antipodal impact of an INI on integrated and episomal HIV-1 cDNAs in vivo. Based on these findings and known biological characteristics of viral episomes, we discuss how integrase inhibition may result in additional indirect antiviral effects that contribute to more rapid HIV-1 decay in HIV/AIDS patients.
Assuntos
Linfócitos T CD4-Positivos/virologia , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Animais , Linhagem Celular , DNA Complementar/genética , DNA Viral/genética , Infecções por HIV/virologia , Inibidores de Integrase de HIV/farmacocinética , HIV-1/fisiologia , Humanos , Pironas/farmacocinética , Pironas/farmacologia , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacologia , Raltegravir Potássico , Ratos , Ratos Transgênicos , Integração Viral/efeitos dos fármacosRESUMO
A series of HIV-1 integrase inhibitors containing a novel metal binding motif consisting of the 8-hydroxy-1,6-naphthyridine core and either an oxadiazole or triazole has been identified. The design of the key structural components was based on a two-metal coordination pharmacophore. This report presents initial structure-activity data that shows the new chelation architecture delivers potent inhibition in both enzymatic and antiviral assays.
Assuntos
Fármacos Anti-HIV/síntese química , Química Farmacêutica/métodos , Inibidores de Integrase de HIV/síntese química , Naftiridinas/síntese química , Oxidiazóis/química , Triazóis/química , Motivos de Aminoácidos , Fármacos Anti-HIV/farmacologia , Quelantes/farmacologia , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacologia , Humanos , Modelos Químicos , Estrutura Molecular , Naftiridinas/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos , Replicação Viral/genéticaRESUMO
The use of a 1,3,4-oxadiazole in combination with an 8-hydroxy-1,6-naphthyridine ring system has been shown to deliver potent enzyme and antiviral activity through inhibition of viral DNA integration. This report presents a detailed structure-activity investigation of the C5 position resulting in low nM potency for several analogs with an excellent therapeutic index.
Assuntos
Fármacos Anti-HIV/síntese química , Química Farmacêutica/métodos , Inibidores de Integrase de HIV/síntese química , Naftiridinas/síntese química , Oxidiazóis/química , Triazóis/química , Motivos de Aminoácidos , Fármacos Anti-HIV/farmacologia , Quelantes/farmacologia , Desenho de Fármacos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacologia , Humanos , Metais/química , Modelos Químicos , Estrutura Molecular , Naftiridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration +/- standard deviation, 8 +/- 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd [binding constant], 6 +/- 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 +/- 0.4 and 5 +/- 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.