A fluorine scan of the phenylamidinium needle of tricyclic thrombin inhibitors: effects of fluorine substitution on pKaand binding affinity and evidence for intermolecular C–F⋯CN interactions

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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 relationships (LFERs) revealed that binding affinity against thrombin is much more affected by a decrease in pKa than the affinity against trypsin. Surprising effects of F-substitutions in the phenylamidinium needle on the pKa value of the tertiary amine centre in the tricyclic scaffold of the inhibitors were observed and subsequently rationalised by X-ray crystallographic analysis and ab initio calculations. Evidence for highly directional intermolecular C–F⋯CN interactions was obtained by analysis of small-molecule X-ray crystal structures and investigations in the Cambridge Structural Database (CSD).