RESUMEN
A series of 2-aryl(pyrrolidin-4-yl)acetic acids were synthesized and their biological activities were evaluated as agonists of S1P receptors. These analogs were able to induce lowering of lymphocyte counts in the peripheral blood of mice and were found to have good overall pharmacokinetic properties in rat.
Asunto(s)
Acetatos/farmacología , Pirrolidinas/farmacología , Receptores de Lisoesfingolípidos/agonistas , Acetatos/síntesis química , Acetatos/química , Animales , Recuento de Linfocitos , Lisofosfolípidos/antagonistas & inhibidores , Ratones , Estructura Molecular , Unión Proteica/efectos de los fármacos , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Esfingosina/análogos & derivados , Esfingosina/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/química , Antagonistas de los Receptores CCR5 , Compuestos Heterocíclicos/química , Pirrolidinas/química , Administración Oral , Animales , Fármacos Anti-VIH/farmacocinética , Células HeLa , Compuestos Heterocíclicos/farmacocinética , Humanos , Pirrolidinas/farmacocinética , Ratas , Receptores CCR5/metabolismoRESUMEN
A series of conformationally constrained 3-(N-alkylamino)propylphosphonic acids were systematically synthesized and their activities as S1P receptor agonists were evaluated. Several pyrrolidine and cyclohexane analogs had S1P receptor profiles comparable to the acyclic lead compound, 3-(N-tetradecylamino)propylphosphonic acid (3), lowered circulating lymphocytes in mice after iv administration and were thus identified as being suitable for further investigations.
Asunto(s)
Diseño de Fármacos , Organofosfonatos/síntesis química , Receptores de Lisoesfingolípidos/agonistas , Animales , Células CHO , Cricetinae , Humanos , Conformación Molecular , Organofosfonatos/química , Organofosfonatos/farmacología , Relación Estructura-ActividadRESUMEN
[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
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.
Asunto(s)
Antagonistas de los Receptores CCR5 , Piperidinas/síntesis química , Piperidinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Células CHO , Quimiocina CCL4 , Cricetinae , Semivida , Células HeLa , Humanos , Enlace de Hidrógeno , Proteínas Inflamatorias de Macrófagos/metabolismo , Piperidinas/farmacocinética , Pirrolidinas/farmacocinética , RatasRESUMEN
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
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.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Antagonistas de los Receptores CCR5 , VIH-1/efectos de los fármacos , Animales , Fármacos Anti-VIH/farmacocinética , Células CHO , Canales de Calcio Tipo L/efectos de los fármacos , Fenómenos Químicos , Química Física , Quimiocina CCL4 , Cricetinae , Semivida , Células HeLa , Humanos , Proteínas Inflamatorias de Macrófagos/antagonistas & inhibidores , Ratas , Receptores CCR5/química , Relación Estructura-ActividadRESUMEN
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.