A fluorine scan of the phenylamidinium needle of tricyclic thrombin inhibitors: effects of fluorine substitution on pKa and binding affinity and evidence for intermolecular C-F...CN interactions.
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 pK(a) value. Both the pK(a) values and the inhibitory constants K(i) 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 pK(a) than the affinity against trypsin. Surprising effects of F-substitutions in the phenylamidinium needle on the pK(a) 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).
Olsen
Jacob
J
Laboratorium fur Organische Chemie, ETH-Honggerberg, HCI, CH-8093 Zurich, Switzerland.
Seiler
Paul
P
Wagner
Björn
B
Fischer
Holger
H
Tschopp
Thomas
T
Obst-Sander
Ulrike
U
Banner
David W
DW
Kansy
Manfred
M
Müller
Klaus
K
Diederich
François
F
D000578:Amidines / Q000737:chemistry*; D000991:Antithrombins / Q000737:chemistry* / Q000378:metabolism; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D005461:Fluorine / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
D000578:Amidines; D000991:Antithrombins; D005461:Fluorine; D014357:Trypsin; D013917:Thrombin