A fluorine scan of the phenylamidinium needle of tricyclic thrombin inhibitors: effects of fluorine substitution on p K a and binding affinity and evidence for …

…, H Fischer, T Tschopp, U Obst-Sander…

Index: Olsen, Jacob; Seiler, Paul; Wagner, Bjoern; Fischer, Holger; Tschopp, Thomas; Obst-Sander, Ulrike; Banner, David W.; Kansy, Manfred; Mueller, Klaus; Diederich, Francois Organic and Biomolecular Chemistry, 2004 , vol. 2, # 9 p. 1339 - 1352

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Citation Number: 65

Abstract

The H-atoms of the phenylamidinium needle of tricyclic thrombin inhibitors, which interacts with Asp189 at the bottom of the selectivity pocket S1 of the enzyme, were systematically exchanged with F-atoms in an attempt to improve the pharmacokinetic properties by lowering the pKa value. Both the pKa values and the inhibitory constants Ki against thrombin and trypsin were decreased upon F-substitution. Interestingly, linear free energy ...