Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator

详细信息    查看全文

• 作者：Martyn Frederickson ; Owen Callaghan ; Gianni Chessari ; Miles Congreve ; Suzanna R. Cowan ; Julia E. Matthews ; Rachel McMenamin ; Donna-Michelle Smith ; Mladen Vinković ; Nicola G. Wallis
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：January 24, 2008
• 年：2008
• 卷：51
• 期：2
• 页码：183 - 186
• 全文大小：660K
• 年卷期：v.51,no.2(January 24, 2008)
• ISSN：1520-4804

文摘

Fragment-based lead discovery has been applied to urokinase-type plasminogen activator (uPA). The (R)-enantiomer of the orally active drug mexiletine 5 (a fragment hit from X-ray crystallographic screening) was the chemical starting point. Structure-aided design led to elaborated inhibitors that retained the key interactions of (R)-5 while gaining extra potency by simultaneously occupying neighboring regions of the active site. Subsequent optimization led to 15, a potent, selective, and orally bioavailable inhibitor of uPA.