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

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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

Drug	Target	Property	Measurement	pH	Temperature (°C)
(2R)-1-(2,6-dimethylphenoxy)propan-2-amine	Urokinase-type plasminogen activator	IC 50 (nM)	>1000000	N/A	N/A	Details
4-(2-AMINOETHOXY)-3,5-DICHLORO-N-[3-(1-METHYLETHOXY)PHENYL]BENZAMIDE	Urokinase-type plasminogen activator	IC 50 (nM)	5200	N/A	N/A	Details
4-(2-aminoethoxy)-N-(2,5-diethoxyphenyl)-3,5-dimethylbenzamide	Urokinase-type plasminogen activator	IC 50 (nM)	1300	N/A	N/A	Details
4-(2-aminoethoxy)-N-(3-chloro-2-ethoxy-5-piperidin-1-ylphenyl)-3,5-dimethylbenzamide	Urokinase-type plasminogen activator	IC 50 (nM)	72	N/A	N/A	Details
4-(2-aminoethoxy)-N-(3-chloro-5-piperidin-1-ylphenyl)-3,5-dimethylbenzamide	Urokinase-type plasminogen activator	IC 50 (nM)	520	N/A	N/A	Details