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rdf:type |
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lifeskim:mentions |
umls-concept:C0003451,
umls-concept:C0013227,
umls-concept:C0015219,
umls-concept:C0019704,
umls-concept:C0021236,
umls-concept:C0185023,
umls-concept:C0237497,
umls-concept:C0243077,
umls-concept:C0441655,
umls-concept:C0681850,
umls-concept:C1314972,
umls-concept:C1522538,
umls-concept:C1550501,
umls-concept:C1702312,
umls-concept:C1706203,
umls-concept:C1880355,
umls-concept:C1947904,
umls-concept:C1999228,
umls-concept:C2349001,
umls-concept:C2697811,
umls-concept:C2825781
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pubmed:issue |
23
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pubmed:dateCreated |
2009-12-3
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pubmed:abstractText |
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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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:BenderJohn AJA,
pubmed-author:ColonnoRichard JRJ,
pubmed-author:D'ArienzoCelia JCJ,
pubmed-author:DiGiugno ParkerDawnD,
pubmed-author:DickerIra BIB,
pubmed-author:EggersBetsy JBJ,
pubmed-author:FanLiL,
pubmed-author:GesenbergChristopheC,
pubmed-author:GongYi-FeiYF,
pubmed-author:HoHsu-TsoHT,
pubmed-author:HuaFangF,
pubmed-author:HugWW,
pubmed-author:JohnsonGrahamG,
pubmed-author:KadowJohn FJF,
pubmed-author:LinPin-FangPF,
pubmed-author:McAuliffeBrian VBV,
pubmed-author:MeanwellNicholas ANA,
pubmed-author:Nowicka-SansBeataB,
pubmed-author:WangTaoT,
pubmed-author:YamanakaGregory AGA,
pubmed-author:YangZhengZ,
pubmed-author:YangZhongZ,
pubmed-author:YinZhiweiZ,
pubmed-author:ZadjuraLisa MLM,
pubmed-author:ZhangZhongxingZ,
pubmed-author:ZhouNannanN
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pubmed:issnType |
Electronic
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pubmed:day |
10
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pubmed:volume |
52
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
7778-87
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pubmed:meshHeading |
pubmed-meshheading:19769332-Animals,
pubmed-meshheading:19769332-Anti-HIV Agents,
pubmed-meshheading:19769332-Cell Line,
pubmed-meshheading:19769332-Drug Discovery,
pubmed-meshheading:19769332-HIV Infections,
pubmed-meshheading:19769332-HIV-1,
pubmed-meshheading:19769332-Humans,
pubmed-meshheading:19769332-Indoles,
pubmed-meshheading:19769332-Models, Molecular,
pubmed-meshheading:19769332-Molecular Conformation,
pubmed-meshheading:19769332-Piperazines,
pubmed-meshheading:19769332-Rats,
pubmed-meshheading:19769332-Reproducibility of Results,
pubmed-meshheading:19769332-Virus Attachment
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pubmed:year |
2009
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pubmed:articleTitle |
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.
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pubmed:affiliation |
Departments of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. tao.wang@bms.com
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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