Factor VIIa inhibitors: A prodrug strategy to improve oral bioavailability

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• 作者：Jennifer R. Riggs ; Aleksandr Kolesnikov ; John Hendrix ; Wendy B. Young ; William D. Shrader ; Dange Vijaykumar ; Robin Stephens ; Liang Liu ; Lin Pan ; Joyce Mordenti et al.
• 关键词：Factor VIIa ; Anticoagulants ; Thrombosis ; Serine protease ; Prodrug ; Amidine ; Amidoxime ; Hydroxy amidine ; Alkoxy amidine ; Carbamate prodrugs ; Pharmacokinetics ; Indole synthesis
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2006
• 出版时间：15 April 2006
• 年：2006
• 卷：16
• 期：8
• 页码：2224-2228
• 全文大小：132 K

文摘

We have developed a series of potent and selective factor VIIa inhibitors based on the 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-biphenyl-3-yl]-succinic acid scaffold. These amidine-containing compounds have low oral bioavailability. Herein, we describe our efforts to improve the oral bioavailability of the parent amidine via a prodrug strategy where the amidine basicity and polarity were reduced with either an alkoxy-amidine or a carbamate prodrug.