Sanofi-Aventis Deutschland GmbH , Industriepark Höchst, Building G878, D-65926 Frankfurt am Main, Germany.
J Med Chem. 2012 Oct 25;55(20):8615-29. doi: 10.1021/jm300771j. Epub 2012 Oct 4.
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-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 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-activity relationship model, a binding hypothesis elucidating the impact of several structural features was developed.
本文描述了一系列新型、高效的基于苯并吡唑谷氨酸哌嗪骨架的 P2Y₁₂ 拮抗剂，可抑制血小板聚集。通过沿该骨架探索取代基的结构要求来研究构效关系，发现 N-乙酰-(S)-脯氨酸环丁基酰胺部分是一个高度有利的基序。将最有利的取代基结合在一起，得到了非常有效的 P2Y₁₂ 拮抗剂，不仅对 P2Y₁₂ 受体具有低纳摩尔结合亲和力，而且在人富含血小板的血浆测定中对血小板聚集的抑制作用也很低，IC₅₀ 值低于 50 nM。利用同源性和三维定量构效关系模型，提出了一个解释几个结构特征影响的结合假设。
