文摘
A series of novel, highly potent P2Y12 antagonists as inhibitors of platelet aggregation based on a phenylpyrazole glutamic acid piperazine backbone is described. Exploration of the structural requirements of the substituents by probing the structure鈥揳ctivity relationship along this backbone led to the discovery of the N-acetyl-(S)-proline cyclobutyl amide moiety as a highly privileged motif. Combining the most favorable substituents led to remarkably potent P2Y12 antagonists displaying not only low nanomolar binding affinity to the P2Y12 receptor but also a low nanomolar inhibition of platelet aggregation in the human platelet rich plasma assay with IC50 values below 50 nM. Using a homology and a three-dimensional quantitative structure鈥揳ctivity relationship model, a binding hypothesis elucidating the impact of several structural features was developed.