title: Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist.
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.
authors: College of Pharmacy, Seoul National University, Seoul 08826, Korea. larica@snu.ac.kr.
authors: Young Ha
authors: YH
authors: Ahn
authors: College of Pharmacy, Seoul National University, Seoul 08826, Korea. leejy@krict.re.kr.|Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. leejy@krict.re.kr.
authors: Joo-Youn
authors: JY
authors: Lee
authors: LG Life Sciences Ltd., R & D Park, Daejeon 305-343, Korea. hdparkc@lgls.com.
authors: Hee Dong
authors: HD
authors: Park
authors: LG Life Sciences Ltd., R & D Park, Daejeon 305-343, Korea. biokth@lgls.com.
authors: Tae Hun
authors: TH
authors: Kim
authors: Medicinal Bioconvergence Research Center, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Suwon 16229, Korea. parkmin2@snu.ac.kr.|Advanced Institutes of Convergence Technology, Seoul National University, Suwon 16229, Korea. parkmin2@snu.ac.kr.
authors: Min Chul
authors: MC
authors: Park
authors: Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. gchoi@krict.re.kr.
authors: Gildon
authors: G
authors: Choi
authors: College of Pharmacy, Seoul National University, Seoul 08826, Korea. sungkim@snu.ac.kr.|Medicinal Bioconvergence Research Center, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Suwon 16229, Korea. sungkim@snu.ac.kr.
authors: Sunghoon
authors: S
authors: Kim
mesh_terms: D000494:Allosteric Regulation; D001792:Blood Platelets / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*
chemical_list: D005343:Fibrinolytic Agents; D009025:Morpholines; C548576:P2RY12 protein, human; C440036:P2RY13 protein, human; D058921:Purinergic P2Y Receptor Antagonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12
keywords: P2Y12 receptor antagonist; antiplatelet; morpholine moiety; ticagrelor