Discovery of a novel series of cyclic urea as potent CCR5 antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 21; pp. 6381 - 6385
• Main Authors: Duan, Maosheng, Kazmierski, Wieslaw M., Tallant, Matt, Jun, Jung Ho, Edelstein, Mark, Ferris, Rob, Todd, Dan, Wheelan, Pat, Xiong, Zhiping
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-11-2011; Elsevier
• Subjects: Antagonist; antagonists; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; antiviral properties; Biological and medical sciences; CCR5; CCR5 Receptor Antagonists; chemistry; Chemokine; Cyclic urea; Drug Discovery; HIV infections; HIV-1; HIV-1 - drug effects; Human immunodeficiency virus 1; Medical sciences; Pharmacokinetics; Pharmacology. Drug treatments; urea; Urea - chemistry; Urea - pharmacology; HIV-1; Chemokine; Antagonist; CCR5; Pharmacokinetics; Cyclic urea; Imidazole derivatives; Sulfone; HIV-1 virus; Monkey; Pyridine derivatives; Primates; Antiviral; Ureas; R configuration; Chemical synthesis; Dog; Fissipedia; Carnivora; Retroviridae; Lentivirus; In vitro; Biological activity; Virus; CCR5 chemokine receptor; In vivo; Vertebrata; Mammalia; Animal; Carboxamide; Benzamide derivatives; Human immunodeficiency virus; Fluorine Organic compounds
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.08.096

A novel series of cyclic urea-based CCR5 antagonists was designed aiming to resolve instability issue in the fasted simulated intestinal fluid (FSIF) associated with the acyclic urea moiety in
1. This class of CCR5 compounds demonstrated high antiviral activities against HIV-1 infection in both HOS and PBL assays. Further evaluation of these compounds indicated that
16-
R
not only substantially enhanced its stability, but also exhibited excellent pharmacokinetics properties.