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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2009 Dec 10; Vol. 52 (23), pp. 7778-87. - Publication Year :
- 2009
-
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.
- Subjects :
- Animals
Anti-HIV Agents chemistry
Anti-HIV Agents pharmacokinetics
Anti-HIV Agents therapeutic use
Cell Line
Drug Discovery
Humans
Models, Molecular
Molecular Conformation
Piperazines chemistry
Piperazines pharmacokinetics
Piperazines therapeutic use
Pyruvic Acid
Rats
Reproducibility of Results
Anti-HIV Agents pharmacology
HIV Infections drug therapy
HIV-1 drug effects
HIV-1 physiology
Indoles chemistry
Piperazines pharmacology
Virus Attachment drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 52
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19769332
- Full Text :
- https://doi.org/10.1021/jm900843g