Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment. 12. Structure-Activity Relationships Associated with 4-Fluoro-6-azaindole Derivatives Leading to the Identification of 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)
Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment. 12. Structure-Activity Relationships Associated with 4-Fluoro-6-azaindole Derivatives Leading to the Identification of 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)
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DOI：
10.1021/jm3016377
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发表时间：
2013-02-28
影响因子：
7.3
通讯作者：
Kadow, John F.
中科院分区：
文献类型：
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作者：
Regueiro-Ren, Alicia;Xue, Qiufen M.;Kadow, John F.
一系列以 4-氟-6-氮杂吲哚为核心杂环的高效 HIV-1 附着抑制剂已被制备出来，其靶向病毒包膜蛋白 gp120。用酰胺 (12a,b)、C-连接杂环 (12c-I) 和 N-连接杂环 (12m-u) 取代氮杂吲哚核心的 7 位，使化合物在假型感染性测定中具有亚纳摩尔效力，并在体内具有良好的药代动力学特征。从最初的 SAR 开发了一个预测模型，其中类似物的效力与氮杂吲哚 7 位取代基通过形成内部氢键或避免排斥性取代模式而采用共面构象的能力相关。 1-(4-苯甲酰哌嗪-1-基)-2-(4-氟-7-[1,2,3]三唑-1-基-1H-吡咯并[2,3-c]吡啶-3-基)乙烷-1,2-二酮 (BMS-585248, 12m) 比之前的临床候选药物 BMS-488043 (1) 表现出显着改善的体外效力和药代动力学特性。预计其在人体中的清除率较低、蛋白质结合程度适中，并且在 40% 人血清存在下 12m 时仍具有良好的效力，因此选择将其用于人体临床研究。
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-I), 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.