A series of highly potent HIV-1 attachment inhibitors with 4-fluoro-6-azaindole core heterocycles that target the viral envelope protein gp120 has been prepared. Substitution in the 7-position of the azaindole core with amides (12a,b), C-linked heterocycles (12c–l), and N-linked heterocycles (12m–u) provided compounds with subnanomolar potency in a pseudotype infectivity assay and good pharmacokinetic profiles in vivo. A predictive model was developed from the initial SAR in which the potency of the analogues correlated with the ability of the substituent in the 7-position of the azaindole to adopt a coplanar conformation by either forming internal hydrogen bonds or avoiding repulsive substitution patterns. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-[1,2,3]triazol-1-yl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-585248, 12m) exhibited much improved in vitro potency and pharmacokinetic properties than the previous clinical candidate BMS-488043 (1). The predicted low clearance in humans, modest protein binding, and good potency in the presence of 40% human serum for 12m led to its selection for human clinical studies.

中文翻译：

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人类免疫缺陷病毒1型（HIV-1）附着的抑制剂。12.与4-氟-6-氮杂吲哚衍生物相关的结构-活性关系导致1-（4-苄酰基哌嗪-1-基）-2-（4-氟-7- [1,2,3]三唑的鉴定-1-基-1 H-吡咯并[2,3- c ]吡啶基-3-基）乙烷-1,2-二酮（BMS-585248）

制备了一系列具有4-氟-6-氮杂吲哚核心杂环的高效HIV-1附着抑制剂，这些抑制剂靶向病毒包膜蛋白gp120。氮杂吲哚核的7位被酰胺（12a，b），C链杂环（12c – l）和N链杂环（12m – u）取代）在假型感染性测定中提供了具有亚纳摩尔效价的化合物，并在体内具有良好的药代动力学特征。从最初的SAR开发了一种预测模型，其中类似物的效力与氮杂吲哚7位上的取代基通过形成内部氢键或避免排斥取代模式而采用共面构象的能力有关。1-（4-苄基哌嗪-1-基）-2-（4-氟-7- [1,2,3]三唑-1-基-1 H-吡咯并[2,3 - c ]吡啶-3-基基）乙烷-1,2-二酮（BMS-585248，12米）表现出多的体外效力和比以前的临床候选BMS-488043的药物动力学性质（提高1）。在40％的人血清中存在12m时，预期的人类低清除率，适度的蛋白质结合以及良好的效力导致了其在人类临床研究中的选择。