A novel lead compound, N-(3-[4-(4-fluorobenzoyl)piperidin-1-yl]propyl)-1-methyl-5-oxo-N-phenylpyrrolidin e-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.

中文翻译：

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CCR5拮抗剂作为抗HIV-1药物。1. 5-氧吡咯烷-3-羧酰胺衍生物的合成和生物学评价。

新型铅化合物N-（3- [4-（4-氟苯甲酰基）哌啶-1-基]丙基）-1-甲基-5-氧代-N-苯基吡咯烷酮e-3-羧酰胺（1）被鉴定为通过使用[（125）I] RANTES和表达CCR5的CHO细胞进行高通量筛选获得CCR5拮抗剂。IC（50）值为1为1.9 microM。为了提高1的结合亲和力，合成了一系列的5-氧吡咯烷-3-羧酰胺。将3,4-二氯取代基引入中央苯环（10i，IC（50）= 0.057 microM; 11b，IC（50）= 0.050 microM）或用1取代5-氧吡咯烷部分的1-甲基发现苄基（12e，IC（50）＝ 0.038microM）对于改善CCR5亲和力是有效的。化合物10i，11b和12e还使用HIV-1包膜介导的膜融合抑制CCR5，IC（50）值分别为0.44、0.19和0.49 microM。