Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment. 5. An Evolution from Indole to Azaindoles Leading to the Discovery of 1-(4-Benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrro

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• 作者：Tao Wang ; Zhiwei Yin ; Zhongxing Zhang ; John A. Bender ; Zhong Yang ; Graham Johnson ; Zheng Yang ; Lisa M. Zadjura ; Celia J. D’ ; Arienzo ; Dawn DiGiugno Parker ; Christophe Gesenberg ; Gregory A. Yamanak
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：December 10, 2009
• 年：2009
• 卷：52
• 期：23
• 页码：7778-7787
• 全文大小：847K
• 年卷期：v.52,no.23(December 10, 2009)
• ISSN：1520-4804

文摘

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.