Respiratory syncytial virus fusion inhibitors. Part 3: Water-soluble benzimidazol-2-one derivatives with antiviral activity in vivo

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 5; pp. 1115 - 1122
• Main Authors: Yu, Kuo-Long, Wang, Xiangdong Alan, Civiello, Rita L., Trehan, Ashok K., Pearce, Bradley C., Yin, Zhiwei, Combrink, Keith D., Gulgeze, H. Belgin, Zhang, Yi, Kadow, Kathleen F., Cianci, Christopher W., Clarke, Junius, Genovesi, Eugene V., Medina, Ivette, Lamb, Lucinda, Wyde, Philip R., Krystal, Mark, Meanwell, Nicholas A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.03.2006; Elsevier
• Subjects: Amines - chemistry; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral; Antiviral agents; Antiviral Agents - adverse effects; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Benzimidazol-2-one derivatives; Benzimidazoles - adverse effects; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biological and medical sciences; Medical sciences; Membrane Fusion - drug effects; Mice; Molecular Structure; Pharmacology. Drug treatments; Rats; Respiratory syncytial virus; Respiratory Syncytial Viruses - drug effects; Respiratory Syncytial Viruses - physiology; Sigmodontinae; Solubility; Structure-Activity Relationship; Water - chemistry; Water-soluble respiratory syncytial virus inhibitors; Benzimidazol-2-one derivatives; Antiviral; Water-soluble respiratory syncytial virus inhibitors; Human respiratory syncytial virus; Rat; Nitrogen heterocycle; Paramyxoviridae; Structure activity relation; Bicyclic compound; Ureas; Subcutaneous administration; Aromatic compound; Pneumovirus; Chemical synthesis; Pneumovirinae; Rodentia; Benzene derivatives; Oral administration; In vitro; Infection; Virus; Water soluble compound; In vivo; Mononegavirales; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Benzimidazole derivatives; Animal; Viral disease; Tertiary amine; Carboxamide; Topical administration
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.11.109

The introduction of acidic and basic functionality into the side chains R and R′ of respiratory syncytial virus (RSV) fusion inhibitors 2 was examined in an effort to identify compounds suitable for evaluation in vivo in the cotton rat model of RSV infection following administration as a small particle aerosol. Several acid-containing compounds demonstrated potent antiviral activity in cell culture and exhibited efficacy in the cotton rat comparable to ribavirin. In a BALB/c mouse model, the amide 2aab reduced virus titers following oral dosing, establishing the potential of this class of RSV fusion inhibitors to interfere with infection in vivo following topical or systemic administration. The introduction of acidic and basic functionality into the side chains of respiratory syncytial virus (RSV) fusion inhibitors was examined in an effort to identify compounds suitable for evaluation in vivo in the cotton rat model of RSV infection following administration as a small particle aerosol. The acidic compounds 2r, 2u, 2v, 2w, 2z, and 2aj demonstrated potent antiviral activity in cell culture and exhibited efficacy in the cotton rat comparable to ribavirin. In a BALB/c mouse model, the oxadiazolone 2aj reduced virus titers following subcutaneous dosing, whilst the ester 2az and amide 2aab exhibited efficacy following oral administration. These results established the potential of this class of RSV fusion inhibitors to interfere with infection in vivo following topical or systemic administration.