Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator
Journal of Medicinal Chemistry2007Vol. 51(2), pp. 183–186
Citations Over TimeTop 16% of 2007 papers
Martyn Frederickson, Owen Callaghan, Gianni Chessari, Miles Congreve, Suzanna Cowan, Julia E. Matthews, Rachel McMenamin, Donna-Michelle Smith, M. Vinković, Nicola G. Wallis
Abstract
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.
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