title: On the design of urokinase-labile prodrugs II. Structure-activity relationships in the urokinase catalyzed hydrolysis of H-GluGlyArg-anilides and -benzylamide.
abstract: Six H-GluGlyArg-anilides with different ortho or para substituents in the aniline group, and H-GluGlyArg-benzylamide were synthesized. KM and kcat for the urokinase-catalyzed hydrolysis of the compounds were determined at 37 degrees C and pH 7.40. In the initial rate measurements, HPLC was used for product quantitation. KM varied between 0.20 mM and 8.9 mM, whereas kcat varied between 0.8s-1 and 16.5s-1 for the investigated substrates. A Hammett plot and a "Charton plot" of the rate data are presented. kcat were, to a minor extent, dependent on the pKa of the leaving group, whereas steric effects had a more marked influence on the overall rate constant. A o-benzyl substituent in the aniline-leaving group exerts less sterical hindrance to the enzymatic hydrolysis than expected from the Charton plot. The significance of the results in relation to the development of urokinase labile dextran prodrugs in discussed.
authors.forename: P
authors.initials: P
authors.lastname: Kurtzhals
authors.forename: C
authors.initials: C
authors.lastname: Larsen
authors.forename: S
authors.initials: S
authors.lastname: Hansen
authors.forename: S
authors.initials: S
authors.lastname: Aasmul-Olsen
authors.forename: F
authors.initials: F
authors.lastname: Widmer
mesh_terms: D015195:Drug Design; D006868:Hydrolysis; D007700:Kinetics; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D011355:Prodrugs; D014568:Urokinase-Type Plasminogen Activator