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J Med Chem. 2012 Oct 25;55(20):8615-29. doi: 10.1021/jm300771j. Epub 2012 Oct 4.

Identification of high-affinity P2Y₁₂ antagonists based on a phenylpyrazole glutamic acid piperazine backbone.

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1
Sanofi-Aventis Deutschland GmbH , Industriepark Höchst, Building G878, D-65926 Frankfurt am Main, Germany.

Abstract

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.

PMID:
22984835
DOI:
10.1021/jm300771j
[Indexed for MEDLINE]

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