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
Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5, Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett. 2006 Mar 1;16(5):1115-22. doi: 10.1016/j.bmcl.2005.11.109. Epub 2005 Dec 20.
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.
研究了将酸性和碱性官能团引入呼吸道合胞病毒（RSV）融合抑制剂侧链的情况，以确定适合在经小颗粒气雾剂给药后，在RSV感染的棉鼠模型中进行体内评估的化合物。酸性化合物2r、2u、2v、2w、2z和2aj在细胞培养中表现出强效抗病毒活性，并且在棉鼠中的疗效与利巴韦林相当。在BALB/c小鼠模型中，恶二唑酮2aj皮下给药后可降低病毒滴度，而酯类化合物2az和酰胺类化合物2aab口服给药后具有疗效。这些结果证实了这类RSV融合抑制剂在局部或全身给药后干扰体内感染的潜力。
