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
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
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
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
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.