Identification of high-affinity P2Y(1)(2) antagonists based on a phenylpyrazole glutamic acid piperazine backbone.

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Zech G, Hessler G, Evers A, Weiss T, Florian P, Just M, Czech J, Czechtizky W, Gorlitzer J, Ruf S, Kohlmann M, Nazare M

Identification of high-affinity P2Y(1)(2) antagonists based on a phenylpyrazole glutamic acid piperazine backbone.

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

PubMed ID

22984835 [ View in PubMed

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Abstract

A series of novel, highly potent P2Y(1)(2) 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(1)(2) antagonists displaying not only low nanomolar binding affinity to the P2Y(1)(2) receptor but also a low nanomolar inhibition of platelet aggregation in the human platelet rich plasma assay with IC(5)(0) 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Ticagrelor	P2Y purinoceptor 12	Ki (nM)	14	N/A	N/A	Details