1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 1; pp. 119 - 123
• Main Authors: Lynch, Christopher L., Willoughby, Christopher A., Hale, Jeffrey J., Holson, Edward J., Budhu, Richard J., Gentry, Amy L., Rosauer, Keith G., Caldwell, Charles G., Chen, Ping, Mills, Sander G., MacCoss, Malcolm, Berk, Scott, Chen, Liya, Chapman, Kevin T., Malkowitz, Lorraine, Springer, Martin S., Gould, Sandra L., DeMartino, Julie A., Siciliano, Salvatore J., Cascieri, Margaret A., 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 06-01-2003; Elsevier
• Subjects: Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; CCR5 Receptor Antagonists; Dogs; Half-Life; Humans; Leukocytes, Mononuclear; Macaca mulatta; Medical sciences; Metabolic Clearance Rate; Pharmacology. Drug treatments; Piperidines - chemistry; Pyrrolidines - chemical synthesis; Pyrrolidines - pharmacokinetics; Pyrrolidines - pharmacology; Radioligand Assay; Rats; Structure-Activity Relationship; Tumor Cells, Cultured; Cyclopropane derivatives; Rat; Sulfone; Nitrogen heterocycle; Organic phosphinate; Alcohol; Clearance; Phosphorus Organic compounds; Pyrrolidine derivatives; Geminal compound; Structure activity relation; Piperidine derivatives; Antiviral; Antagonist; Chemical synthesis; Rodentia; Elimination; Retroviridae; Lentivirus; In vitro; Virus; CCR5 chemokine receptor; Vertebrata; Mammalia; Side chain; Animal; Cyclobutane derivatives; Benzenic compound; Fluorine Organic compounds; Human immunodeficiency virus; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00829-6

The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist
1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones,
gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.
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