1,3,4 trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains

A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC 95=50 nM). Compound 4a also has improved PK properties relative to 1. Optimizatio...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2003-02, Vol.13 (3), p.427-431
Hauptverfasser:	Willoughby, Christopher A, Rosauer, Keith G, Hale, Jeffery J, Budhu, Richard J, Mills, Sander G, Chapman, Kevin T, MacCoss, Malcolm, 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:	Artikel
Sprache:	eng
Schlagworte:	Animals Anti-HIV Agents - chemical synthesis Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences CCR5 Receptor Antagonists Chemokine CCL4 CHO Cells Cricetinae Half-Life HeLa Cells Humans Hydrogen Bonding Macrophage Inflammatory Proteins - metabolism Medical sciences Pharmacology. Drug treatments Piperidines - chemical synthesis Piperidines - pharmacokinetics Piperidines - pharmacology Pyrrolidines - chemical synthesis Pyrrolidines - pharmacokinetics Pyrrolidines - pharmacology Rats
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Beschreibung
Zusammenfassung:	A new class of 4-(aminoheterocycle)piperidine derived 1,3,4 trisubstituted pyrrolidine CCR5 antagonists is reported. Compound 4a is shown to have good binding affinity (1.8 nM) and antiviral activity in PBMC's (IC 95=50 nM). Compound 4a also has improved PK properties relative to 1. Optimization of 4(3-arylpropyl)piperidine derived 1,3,4-trisubstituted pyrrolidine CCR5 antagonists is reported.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(02)00988-5