Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.

Article Details

Citation

Frederickson M, Callaghan O, Chessari G, Congreve M, Cowan SR, Matthews JE, McMenamin R, Smith DM, Vinkovic M, Wallis NG

Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.

J Med Chem. 2008 Jan 24;51(2):183-6. doi: 10.1021/jm701359z. Epub 2007 Dec 29.

PubMed ID
18163548 [ View in 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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(2R)-1-(2,6-dimethylphenoxy)propan-2-amineUrokinase-type plasminogen activatorIC 50 (nM)>1000000N/AN/ADetails
4-(2-AMINOETHOXY)-3,5-DICHLORO-N-[3-(1-METHYLETHOXY)PHENYL]BENZAMIDEUrokinase-type plasminogen activatorIC 50 (nM)5200N/AN/ADetails
4-(2-aminoethoxy)-N-(2,5-diethoxyphenyl)-3,5-dimethylbenzamideUrokinase-type plasminogen activatorIC 50 (nM)1300N/AN/ADetails
4-(2-aminoethoxy)-N-(3-chloro-2-ethoxy-5-piperidin-1-ylphenyl)-3,5-dimethylbenzamideUrokinase-type plasminogen activatorIC 50 (nM)72N/AN/ADetails
4-(2-aminoethoxy)-N-(3-chloro-5-piperidin-1-ylphenyl)-3,5-dimethylbenzamideUrokinase-type plasminogen activatorIC 50 (nM)520N/AN/ADetails