TY - JOUR
T1 - Identification of a new morpholine scaffold as a P2Y12 receptor antagonist
AU - Ahn, Young Ha
AU - Lee, Joo Youn
AU - Park, Hee Dong
AU - Kim, Tae Hun
AU - Park, Min Chul
AU - Choi, Gildon
AU - Kim, Sunghoon
N1 - Publisher Copyright:
© 2016 by the authors; licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 2016/9
Y1 - 2016/9
N2 - 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.
AB - 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.
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U2 - 10.3390/molecules21091114
DO - 10.3390/molecules21091114
M3 - Article
C2 - 27563870
AN - SCOPUS:84987853258
VL - 21
JO - Molecules
JF - Molecules
SN - 1420-3049
IS - 9
M1 - 1114
ER -