P3 optimization of functional potency, in vivo efficacy and oral bioavailability in 3-aminopyrazinone thrombin inhibitors bearing non-charged groups at the P1 position

Although the S3 pocket of the thrombin active site is lined with lipophilic amino acid residues, the accommodation of polarity within the lipophilic P3 moiety of small molecule inhibitors is possible provided that the polar functionality is capable of pointing away from the binding pocket outwards toward solvent while simultaneously allowing the lipophilic portion of the P3 ligand to interact with the S3 amino acid residues. Manipulation of this motif provided the means to effect optimization of functional potency, in vivo antithrombotic efficacy and oral bioavailability in a series of 3-aminopyrazinone thrombin inhibitors which contained non-charged groups at the P1 position.

Graphical abstractA series of 3-aminopyrazinone P2 thrombin inhibitors bearing non-charged groups (X, Y) at the P1 benzylamino position was optimized with respect to functional potency, in vivo efficacy and oral bioavailability by manipulation of polarity at the P3 pyridine position (Z = H, piperidine; Z = O, pyridine-N-oxide).Figure optionsDownload full-size imageDownload as PowerPoint slide