title: 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.
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 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).
authors.affiliation: Laboratorium fur Organische Chemie, ETH-Honggerberg, HCI, CH-8093 Zurich, Switzerland.
authors.forename: Jacob
authors.initials: J
authors.lastname: Olsen
authors.forename: Paul
authors.initials: P
authors.lastname: Seiler
authors.forename: Björn
authors.initials: B
authors.lastname: Wagner
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschopp
authors.forename: Ulrike
authors.initials: U
authors.lastname: Obst-Sander
authors.forename: David W
authors.initials: DW
authors.lastname: Banner
authors.forename: Manfred
authors.initials: M
authors.lastname: Kansy
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: 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
chemical_list: D000578:Amidines; D000991:Antithrombins; D005461:Fluorine; D014357:Trypsin; D013917:Thrombin