Wang Tao, Yin Zhiwei, Zhang Zhongxing, Bender John A, Yang Zhong, Johnson Graham, Yang Zheng, Zadjura Lisa M, D'Arienzo Celia J, DiGiugno Parker Dawn, Gesenberg Christophe, Yamanaka Gregory A, Gong Yi-Fei, Ho Hsu-Tso, Fang Hua, Zhou Nannan, McAuliffe Brian V, Eggers Betsy J, Fan Li, Nowicka-Sans Beata, Dicker Ira B, Gao Qi, Colonno Richard J, Lin Pin-Fang, Meanwell Nicholas A, Kadow John F
Departments of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
J Med Chem. 2009 Dec 10;52(23):7778-87. doi: 10.1021/jm900843g.
Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.
制备并表征了从筛选先导化合物1-(4-苯甲酰基哌嗪-1-基)-2-(1H-吲哚-3-基)乙烷-1,2-二酮(1)衍生而来的氮杂吲哚衍生物，以评估它们作为HIV-1附着抑制剂的潜力。通过用氮原子系统取代吲哚部分苯环中每个未稠合的碳原子，得到了四种不同的氮杂吲哚衍生物，它们显示出明显的抗病毒活性构效关系，并且所有衍生物在药学性质上都有显著改善。对这些氮杂吲哚先导化合物进行优化，结果鉴定出两种进入临床研究的化合物：(R)-1-(4-苯甲酰基-2-甲基哌嗪-1-基)-2-(4-甲氧基-1H-吡咯并[2,3-b]吡啶-3-基)乙烷-1,2-二酮(BMS-377806, 3)和1-(4-苯甲酰基哌嗪-1-基)-2-(4,7-二甲氧基-1H-吡咯并[2,3-c]吡啶-3-基)乙烷-1,2-二酮(BMS-488043, 4)。在一项初步临床研究中，4作为单一疗法给药8天，降低了HIV-1感染受试者的病毒血症，为这一作用机制类别提供了概念验证。
