2. Academic Validation
  3. 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-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a drug candidate that demonstrates antiviral activity in HIV-1-infected subjects

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-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a drug candidate that demonstrates antiviral activity in HIV-1-infected subjects

  • J Med Chem. 2009 Dec 10;52(23):7778-87. doi: 10.1021/jm900843g.
Tao Wang 1,  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 Yamanaka,  Yi-Fei Gong,  Hsu-Tso Ho,  Hua Fang,  Nannan Zhou,  Brian V McAuliffe,  Betsy J Eggers,  Li Fan,  Beata Nowicka-Sans,  Ira B Dicker,  Qi Gao,  Richard J Colonno,  Pin-Fang Lin,  Nicholas A Meanwell,  John F Kadow
Affiliations

Affiliation

  • 1 Departments of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. tao.wang@bms.com
PMID: 19769332 DOI: 10.1021/jm900843g
Abstract

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.

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