RESUMO
[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Propionatos/farmacologia , Pirrolidinas/farmacologia , Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Propionatos/farmacocinética , Pirrolidinas/farmacocinéticaRESUMO
A series of 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Compostos Heterocíclicos/química , Pirrolidinas/química , Administração Oral , Animais , Fármacos Anti-HIV/farmacocinética , Células HeLa , Compostos Heterocíclicos/farmacocinética , Humanos , Pirrolidinas/farmacocinética , Ratos , Receptores CCR5/metabolismoRESUMO
Synthesis of analogs containing more rigid bicyclic piperidine replacements for the 4-benzyloxycarbonyl-(ethyl)amino-piperidine moiety of the CCR5 antagonist structure, 1, is described. Although similar binding affinity to the lead was achieved with some analogs they were overall less potent anti-HIV agents suggesting that other features besides CCR5 binding are required for good anti-viral activity.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Sulfonas/síntese química , Fármacos Anti-HIV/farmacologia , Butanos/síntese química , Butanos/farmacologia , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Piperidinas/síntese química , Piperidinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/farmacologia , Vírus/efeitos dos fármacosRESUMO
A series of CCR5 antagonists containing bicyclic isoxazolidines was generated through a nitrone mediated cycloaddition with olefins bearing the preferred pharmacophores previously described. Potent antagonists (3 and 16) were generated with enhanced affinity for the CCR5 receptor while maintaining antiviral activity against HIV.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Isoxazóis/síntese química , Fármacos Anti-HIV/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Testes de Sensibilidade Microbiana , Conformação Molecular , Ligação Proteica , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Incorporation of acidic functional groups into a lead CCR5 antagonist identified from a targeted combinatorial library resulted in compounds with enhanced anti-HIV-1 activity and attenuated L-type calcium channel affinity.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Animais , Fármacos Anti-HIV/farmacocinética , Células CHO , Canais de Cálcio Tipo L/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Quimiocina CCL4 , Cricetinae , Meia-Vida , Células HeLa , Humanos , Proteínas Inflamatórias de Macrófagos/antagonistas & inibidores , Ratos , Receptores CCR5/química , Relação Estrutura-AtividadeRESUMO
Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Pirrolidinas/síntese química , Acetatos/química , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Divisão Celular/efeitos dos fármacos , Células HeLa , Humanos , Piperidinas/síntese química , Piperidinas/farmacologia , Pirrolidinas/química , Relação Estrutura-AtividadeRESUMO
Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Piperidinas/síntese química , Piperidinas/farmacocinética , Animais , Fármacos Anti-HIV/química , Divisão Celular/efeitos dos fármacos , Células HeLa , Humanos , Estrutura Molecular , Piperidinas/química , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Fármacos Anti-HIV/farmacocinética , Células CHO , Permeabilidade da Membrana Celular , Fenômenos Químicos , Físico-Química , Quimiocina CCL4 , Cricetinae , Células HeLa , Humanos , Indicadores e Reagentes , Proteínas Inflamatórias de Macrófagos/antagonistas & inibidores , Pirrolidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC(95)=50 nM). Compound 4a also has improved PK properties relative to 1.
Assuntos
Antagonistas dos Receptores CCR5 , Piperidinas/síntese química , Piperidinas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Células CHO , Quimiocina CCL4 , Cricetinae , Meia-Vida , Células HeLa , Humanos , Ligação de Hidrogênio , Proteínas Inflamatórias de Macrófagos/metabolismo , Piperidinas/farmacocinética , Pirrolidinas/farmacocinética , RatosRESUMO
Cellular proliferation of HIV-1 requires the cooperative assistance of both the CCR5 and CD4 receptors. Our medicinal chemistry efforts in this area have resulted in the identification of N-alkyl piperidine sulfones as CCR5 antagonists. These compounds display potent binding and show antiviral properties in HIV-1 spread cell-based assays.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Sulfonas/síntese química , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Antígenos CD4/metabolismo , Linhagem Celular , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Piperidinas/química , Receptores CCR5/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/farmacologiaRESUMO
Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Piperidinas/síntese química , Piperidinas/farmacocinética , Acetatos/química , Acetatos/farmacocinética , Administração Oral , Animais , Fármacos Anti-HIV/química , Disponibilidade Biológica , Cães , Células HeLa , Humanos , Macaca mulatta , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperidinas/química , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Piperidinas/química , Piperidinas/farmacocinética , Pirazóis/química , Animais , Fármacos Anti-HIV/síntese química , Disponibilidade Biológica , Cães , Células HeLa , Humanos , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperidinas/síntese química , Pirazóis/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.