Identification of High-Affinity P2Y12 Antagonists Based on a Phenylpyrazole Glutamic Acid Piperazine Backbone

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• 作者：Gernot Zech ; Gerhard Hessler ; Andreas Evers ; Tilo Weiss ; Peter Florian ; Melitta Just ; J枚rg Czech ; Werngard Czechtizky ; Jochen G枚rlitzer ; Sven Ruf ; Markus Kohlmann ; Marc Nazar茅
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 25, 2012
• 年：2012
• 卷：55
• 期：20
• 页码：8615-8629
• 全文大小：570K
• 年卷期：v.55,no.20(October 25, 2012)
• ISSN：1520-4804

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.