RESUMO
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
Synthesis of a series of 5-substituted as well as 5,7-disubstituted 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo[1,5-a]pyridin-7-amines 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 to or better than acyclovir are described.
Assuntos
Aciclovir/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Herpesviridae/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Antivirais/química , Técnicas de Química Combinatória , Humanos , Estrutura Molecular , Pirazóis/química , Piridinas/química , 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.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Naftiridinas/farmacologia , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Células Cultivadas , Farmacorresistência Viral , Sinergismo Farmacológico , Integrase de HIV/genética , Inibidores da Protease de HIV/farmacologia , HIV-1/enzimologia , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/virologia , Testes de Sensibilidade Microbiana/métodos , Mutação , Inibidores da Transcriptase Reversa/farmacologia , Integração Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
A recently disclosed series of pyrazolo[1,5-a]pyridine inhibitors of herpes virus replication has been closely examined herein for effects of the C3 substituent on antiviral activity. Significant changes in activity are observed by alterations of the heteroatom basicity and orientation of the group at C3. These results in combination with previous studies have served to further elaborate the minimal pharmacophore required for potency of this novel series of antiviral agents. During the course of these studies, several novel synthetic approaches were developed and are described.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Herpesviridae/efeitos dos fármacos , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Herpesviridae/fisiologia , Humanos , Piridinas/química , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
A novel series of potent C-6 substituted pyrazolo[1,5-a]pyridine inhibitors of herpes simplex viruses has been identified. A synthetic methodology was developed involving functionalization of a C-6 trifluoromethyl pyrazolo[1,5-a]pyridine to allow facile access to a diverse set of analogues from common late stage intermediates. The expansion of the SAR of this series at the 6 position allows for modifications to developability parameters such as clogP, while maintaining potency comparable to acyclovir.
Assuntos
Herpesviridae/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Linhagem Celular , Chlorocebus aethiops , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/toxicidade , Piridinas/síntese química , Piridinas/toxicidade , Relação Estrutura-AtividadeRESUMO
Herpesviruses are a significant source of human disease; amongst these herpes simplex virus 1 (HSV-1) and HSV-2 are very prevalent and cause recurrent infections. We recently identified a pyrazolo[1,5-a]pyridine scaffold that showed promising activity against HSV-1 and HSV-2 in Vero cell antiviral assays. Here, we describe the synthesis and anti-herpetic activity of several 3-pyrimidinyl-2-phenylpyrazolo[1,5-a]pyridines with differing 2-phenyl substitution patterns. Approaches to rapidly access a number of analogs with different 2-phenyl substitution patterns are outlined. Several of the compounds described have comparable activity to acyclovir against HSV-1 and HSV-2.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Fenol/química , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Animais , Antivirais/química , Linhagem Celular , Chlorocebus aethiops , Humanos , Testes de Sensibilidade Microbiana , Pirazóis/química , Piridinas/química , Relação Estrutura-Atividade , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
A novel series of potent pyrazolo[1,5-a]pyridine inhibitors of herpes simplex virus 1 replication have been identified. Several complimentary synthetic methods were developed to allow facile access to a diverse set of analogs from common late stage intermediates. Detailed examination of the amine substituents at the C2' position of the pyrimidine and C7 position of the core pyrazolopyridine is described. The antiviral data suggests that non-polar amines are preferred for optimal activity. Additionally, the 2' position has been shown to require an NH group to retain activity levels similar to that of the gold standard acyclovir.
Assuntos
Aminas/química , Antivirais/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Chlorocebus aethiops , Herpesviridae/efeitos dos fármacos , Herpesvirus Cercopitecino 1/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Células VeroRESUMO
A series of 7-substituted-3-cyclobutylamino-4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives has been synthesized and evaluated as K(ATP) channel agonists using the inside-out excised patch clamp technique. The most active compounds were approximately 20-fold more potent than diazoxide in opening K(ATP) channels. A linear relationship exists between the potency of the compound and the sigma value of the 7-substituent with electron-withdrawing groups exhibiting higher activity. These compounds may be useful in modulating insulin release from pancreatic beta-cells and in diseases associated with hyperinsulinemia.