Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-pyrrolidin-1-yl-acetic acid antagonists of the human CCR5 chemokine receptor

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 13; pp. 3419 - 3424
• Main Authors: Shankaran, K., Donnelly, Karla L., Shah, Shrenik K., Guthikonda, Ravindra N., MacCoss, Malcolm, Mills, Sander G., Gould, Sandra L., Malkowitz, Lorraine, Siciliano, Salvatore J., Springer, Martin S., Carella, Anthony, Carver, Gwen, Hazuda, Daria, Holmes, Karen, Kessler, Joseph, Lineberger, Janet, Miller, Michael D., Emini, Emilio A., Schleif, William A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 05-07-2004; Elsevier
• Subjects: Acetates - chemistry; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; CCR5 Receptor Antagonists; Cell Division - drug effects; HeLa Cells; HIV-1 - drug effects; Humans; Medical sciences; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - pharmacology; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Structure-Activity Relationship; Human; Imidazole derivatives; Five membered ring; HIV-1 virus; Thiazole derivatives; Retroviridae; Oxygen heterocycle; Lentivirus; In vitro; Virus; CCR5 chemokine receptor; Structure activity relation; Carboxylic acid; Six membered ring; Piperidine derivatives; Antiviral; Human immunodeficiency virus; Antagonist; Chemical synthesis; Oxazole derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.04.078

A series of pyrrolidineacetic acid derivatives (
1) was prepared and assayed for their CCR5 receptor affinity, anti-HIV-1 activity in a HeLa cell-based assay, and oral bioavailability in the rat. These pyrrolidineacetic acid analogs (R
2) incorporated a variety of 4-heterocyclic piperidiene derivatives (R
1) to optimize these potential antiviral properties.
Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.