CCR5 antagonists: bicyclic isoxazolidines as conformationally constrained N-1-substituted pyrrolidines

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 4; pp. 677 - 679
• Main Authors: Lynch, Christopher L, Gentry, Amy L, Hale, Jeffrey J, Mills, Sander G, MacCoss, Malcolm, Malkowitz, Lorraine, Springer, Martin S, Gould, Sandra L, DeMartino, Julie A, Siciliano, Salvatore J, Cascieri, Margaret A, Doss, George, Carella, Anthony, Carver, Gwen, Holmes, Karen, Schleif, William A, Danzeisen, Renee, Hazuda, Daria, Kessler, Joseph, Lineberger, Janet, Miller, Michael, Emini, Emilio A
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 25-02-2002; Elsevier
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; CCR5 Receptor Antagonists; HIV-1 - drug effects; Humans; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Medical sciences; Microbial Sensitivity Tests; Molecular Conformation; Pharmacology. Drug treatments; Protein Binding; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Structure-Activity Relationship; Nitrogen heterocycle; Retroviridae; Tricyclic compound; Lentivirus; In vitro; Spiran; Virus; CCR5 chemokine receptor; Structure activity relation; Piperidine derivatives; Antiviral; Benzenic compound; Antagonist; Human immunodeficiency virus; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00835-6

A series of CCR5 antagonists containing bicyclic isoxazolidines was generated through a nitrone mediated cycloaddition with olefins bearing the preferred pharmacophores previously described. Potent antagonists (
3 and
16) were generated with enhanced affinity for the CCR5 receptor while maintaining antiviral activity against HIV.
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