Download MendeleyFragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator.
Frederickson, M., Callaghan, O., Chessari, G., Congreve, M., Cowan, S.R., Matthews, J.E., Mcmenamin, R., Smith, D., Vinkovic, M., Wallis, N.G.(2008) J Med Chem 51: 183
- PubMed: 18163548
- DOI: https://doi.org/10.1021/jm701359z
- Primary Citation of Related Structures:
2VIN, 2VIO, 2VIP, 2VIQ, 2VIV, 2VIW - PubMed 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.
Organizational Affiliation:
Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. m.frederickson@astex-therapeutics.com
