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Molecules 2016, 21(9), 1114; doi:10.3390/molecules21091114

Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist

1
College of Pharmacy, Seoul National University, Seoul 08826, Korea
2
Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
3
LG Life Sciences Ltd., R & D Park, Daejeon 305-343, Korea
4
Medicinal Bioconvergence Research Center, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Suwon 16229, Korea
5
Advanced Institutes of Convergence Technology, Seoul National University, Suwon 16229, Korea
6
Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 29 June 2016 / Revised: 11 August 2016 / Accepted: 22 August 2016 / Published: 24 August 2016
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [2034 KB, uploaded 24 August 2016]   |  

Abstract

The P2Y12 receptor is critical for platelet activation and is an attractive drug target for the prevention of atherothrombotic events. Despite the proven antithrombotic efficacy of P2Y12 inhibitors, these thienopyridine scaffolds are prodrugs that lack important features of the ideal antithrombotic agent. For this reason, ticagrelor—a new chemical class of P2Y12 receptor antagonist—was developed, but it can cause shortness of breath and various types of bleeding. Moreover, ticagrelor is a cytochrome P450 3A4 substrate/inhibitor and, therefore, caution should be exercised when it is used concomitantly with strong CYP3A4 inducers/inhibitors. There is a need for novel P2Y12 receptor antagonist scaffolds that are reversible and have high efficacy without associated side effects. Here, we describe a novel antagonist containing a morpholine moiety that was identified by screening libraries of commercially available compounds. The molecule, Compound E, acted on P2Y12, but not P2Y1 and P2Y13, and exhibited pharmacological characteristics that were distinct from those of ticagrelor, acting instead on P2Y12 via an allosteric mechanism. These results provide a basis for the development/optimization of a new class of P2Y12 antagonists. View Full-Text
Keywords: P2Y12 receptor antagonist; antiplatelet; morpholine moiety; ticagrelor P2Y12 receptor antagonist; antiplatelet; morpholine moiety; ticagrelor
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Ahn, Y.H.; Lee, J.-Y.; Park, H.D.; Kim, T.H.; Park, M.C.; Choi, G.; Kim, S. Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist. Molecules 2016, 21, 1114.

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