RESUMEN
Replacement of the 5-oxopyrrolidin-3-yl fragment in the previously reported lead structure with a 1-acetylpiperidin-4-yl group led to the discovery of a novel series of potent CCR5 antagonists. Introduction of small hydrophobic substituents on the central phenyl ring increased the binding affinity, providing low to sub-nanomolar CCR5 antagonists. The selected compound 11f showed excellent antiviral activity against CCR5-using HIV-1 replication in human peripheral blood mononuclear cells (EC50=0.59 nM) and an acceptable pharmacokinetic profile in dogs.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Antagonistas de los Receptores CCR5 , Piperidinas/síntesis química , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Células CHO , Células COS , Chlorocebus aethiops , Cricetinae , Cricetulus , Perros , VIH-1/efectos de los fármacos , Humanos , Masculino , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacología , Ratas , Receptores CCR5/química , Relación Estructura-ActividadRESUMEN
A novel lead compound, N-(3-[4-(4-fluorobenzoyl)piperidin-1-yl]propyl)-1-methyl-5-oxo-N-phenylpyrrolidine-3-carboxamide (1), was identified as a CCR5 antagonist by high-throughput screening using [(125)I]RANTES and CCR5-expressing CHO cells. The IC(50) value of 1 was 1.9 microM. In an effort to improve the binding affinity of 1, a series of 5-oxopyrrolidine-3-carboxamides was synthesized. Introduction of 3,4-dichloro substituents to the central phenyl ring (10i, IC(50)=0.057 microM; 11b, IC(50)=0.050 microM) or replacing the 1-methyl group of the 5-oxopyrrolidine moiety with a 1-benzyl group (12e, IC(50)=0.038 microM) was found to be effective for improving CCR5 affinity. Compound 10i, 11b, and 12e also inhibited CCR5-using HIV-1 envelope-mediated membrane fusion with IC(50) values of 0.44, 0.19, and 0.49 microM, respectively.