Naphthamidine Urokinase Plasminogen Activator Inhibitors (I), (II) with Improved Pharmacokinetic Properties.

ChemInform ◽  
2005 ◽  
Vol 36 (18) ◽  
Author(s):  
Milan Bruncko ◽  
et al. et al.
Keyword(s):  
Plasminogen Activator ◽  
Urokinase Plasminogen Activator ◽  
Plasminogen Activator Inhibitors ◽  
Pharmacokinetic Properties

Naphthamidine urokinase plasminogen activator inhibitors with improved pharmacokinetic properties

2005 ◽  
Vol 15 (1) ◽  
pp. 93-98 ◽  
Author(s):  
Milan Bruncko ◽  
William J. McClellan ◽  
Michael D. Wendt ◽  
Daryl R. Sauer ◽  
Andrew Geyer ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Urokinase Plasminogen Activator ◽  
Plasminogen Activator Inhibitors ◽  
Pharmacokinetic Properties

Structure-Based design, synthesis and sAR of a novel series of thiopheneamidine urokinase plasminogen activator inhibitors

2001 ◽  
Vol 11 (11) ◽  
pp. 1379-1382 ◽  
Author(s):  
Nalin L. Subasinghe ◽  
Carl Illig ◽  
James Hoffman ◽  
M.Jonathan Rudolph ◽  
Kenneth J. Wilson ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Urokinase Plasminogen Activator ◽  
Plasminogen Activator Inhibitors ◽  
Design Synthesis

Expression of plasminogen activator inhibitors type 1 and type 3 and urokinase plasminogen activator protein and mRNA in breast cancer

2007 ◽  
Vol 120 (5) ◽  
pp. 753-762 ◽  
Author(s):  
Remedios Castelló ◽  
Jose M. Landete ◽  
Francisco España ◽  
Carlos Vázquez ◽  
Carlos Fuster ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasminogen Activator ◽  
Urokinase Plasminogen Activator ◽  
Plasminogen Activator Inhibitors ◽  
Activator Protein ◽  
Type 3

Expression and Characterization of Clustered Charge-to-Alanine Mutants of Low Mr Single-Chain Urokinase-Type Plasminogen Activator

1994 ◽  
Vol 71 (01) ◽  
pp. 134-140 ◽  
Author(s):  
S Ueshima ◽  
P Holvoet ◽  
H R Lijnen ◽  
L Nelles ◽  
V Seghers ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Solvent Accessibility ◽  
Site Directed Mutagenesis ◽  
Clot Lysis ◽  
Wild Type ◽  
Single Chain ◽  
Charged Amino Acids ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Pharmacokinetic Properties

SummaryIn an effort to modify the fibrinolytic and/or pharmacokinetic properties of recombinant low M r single-chain urokinase-type plasminogen activator (rscu-PA-32k), mutants were prepared by site-directed mutagenesis of clusters of charged amino acids with the highest solvent accessibility. The following mutants of rscu-PA-32k were prepared: LUK-2 (Lys 212, Glu 213 and Asp 214 to Ala), LUK-3 (Lys 243 and Asp 244 to Ala), LUK-4 (Arg 262, Lys 264, Glu 265 and Arg 267 to Ala), LUK-5 (Lys 300, Glu 301 and Asp 305 to Ala) and LUK-6 (Arg 400, Lys 404, Glu 405 and Glu 406 to Ala).The rscu-PA 32k moictic3 were expressed in High Five Ttichoplasiani cells, and purified to humugciicily from the conditioned cell culture medium, with recoveries of 0.8 to 3.7 mg/1. The specific fibrinolytic activities (220,000 to 300,000 IU/mg), the rates of plasminogen activation by the single-chain moieties and the rates of conversion In lwo chain moieties by plasmin were comparable for mutant and wild-type rscu PA 32k moieties, with the exception of LUK-5 which was virtually inactive. Equi-effective lysis (50% in 2 h) of 60 pi 125I-fibrin labeled plasma clots submerged in 0.5 ml normal human plasma was obtained with 0.7 to 0.8 μg/ml of wild-type or mutant rscu-PA-3?.k, except with LUK-5 (no significant lysis with 16 pg/ml). Following bolus injection in hamsters, all rscu-PA-32k moieties had a comparably rapid plasma clearance (1.3 to 2.7 ml/min), as a result of a short initial half-life (1.4 to 2.5 min). In hamsters with pulmonary embolism, continuous intravenous infusion over 60 min at a dose of 1 mg/kg, resulted in 53 to 72% clot lysis with the mutants, but only 23% with LUK-5, as compared to 36% for wild-type rscu-PA-32k.These data indicate that clustered charge-to-alanine mutants of rscu-PA-32k, designed to eliminate charged regions with the highest solvent accessibility, do not have significantly improved functional, fibrinolytic or pharmacokinetic properties.

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