Identification of High-Affinity P2Y(12) Antagonists Based on a Phenylpyrazole Glutamic Acid Piperazine Backbone

作者：Zech Gernot; Hessler Gerhard; Evers Andreas; Weiss Tilo; Florian Peter; Just Melitta; Czech Joerg; Czechtizky Werngard; Goerlitzer Jochen; Ruf Sven; Kohlmann Markus; Nazare Marc^*

来源：Journal of Medicinal Chemistry, 2012, 55(20): 8615-8629.

DOI：10.1021/jm300771j

A series of novel, highly potent P2Y(12) 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-activity 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 P2Y(12) antagonists displaying not only low nanomolar binding affinity to the P2Y(12) 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-activity relationship model, a binding hypothesis elucidating the impact of several structural features was developed.

• 出版日期2012-10-25