RESUMEN
[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.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , Propionatos/farmacología , Pirrolidinas/farmacología , Fármacos Anti-VIH/farmacocinética , Disponibilidad Biológica , Propionatos/farmacocinética , Pirrolidinas/farmacocinéticaRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Antagonistas de los Receptores CCR5 , Pirrolidinas/farmacocinética , Animales , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Perros , Semivida , Humanos , Leucocitos Mononucleares , Macaca mulatta , Tasa de Depuración Metabólica , Piperidinas/química , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , VIH-1/efectos de los fármacos , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Fármacos Anti-VIH/farmacocinética , Células CHO , Permeabilidad de la Membrana Celular , Fenómenos Químicos , Química Física , Quimiocina CCL4 , Cricetinae , Células HeLa , Humanos , Indicadores y Reactivos , Proteínas Inflamatorias de Macrófagos/antagonistas & inhibidores , Pirrolidinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
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.