A Fluorine Scan at the Catalytic Center of Thrombin: CF, COH, and COMe Bioisosterism and Fluorine Effects on p<i>K</i>_a and log <i>D</i> Values

Abstract

Abstract A series of 16 tricyclic thrombin inhibitors was prepared by using the 1,3‐dipolar cycloaddition of azomethine ylides derived from 3‐ or 4‐hydroxyproline and 4‐bromobenzaldehyde, with N ‐(4‐fluorobenzyl)maleimide as the key step. The terminal pyrrolidine ring of the inhibitors was systematically substituted to explore the potential bioisosteric behavior of CF, COH, and COMe residues pointing into the environment of the catalytic center of a serine protease. X‐ray crystal structure analyses revealed a distinct puckering preference of this ring. Substitution by F, HO, and MeO has a strong effect on the basicity of the adjacent pyrrolidine nitrogen center which originates from two σ‐inductive pathways between this center and the electronegative O and F atoms. gem ‐Difluorination decreases the p K a value of this tertiary amine center to &lt;2, making the conjugated ammonium ion a moderately strong acid. Unexpectedly, F substitution next to the nitrogen center reduced the lipophilicity of the ligands, as revealed by measurements of the logarithmic partition coefficient log D . The biological assays showed that all compounds are thrombin inhibitors with activities between K i =0.08 and 2.17 μ M . Bioisosteric behavior of F, HO, and MeO substituents was observed. Their electronegative F and O atoms undergo energetically similar polar interactions with positively polarized centers, such as the N atom of His 57 which is hydrogen bonded to the catalytic Ser 195. However, for energetically similar polar interactions of CF, COH, and COMe to occur, sufficient space is necessary for the accommodation of the Me group of the COMe residue, and a H‐bond acceptor must be present to prevent unfavorable desolvation of the COH residue.

Keywords

Affiliated Institutions

• Johannes Gutenberg University Mainz DE
• ETH Zurich CH
• Roche (Switzerland) CH

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