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Antithrombotic P2Y12 Receptor Antagonists: Recent Developments in Drug Discovery

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Antithrombotic P2Y12 Receptor Antagonists: Recent Developments in Drug Discovery Drug Discovery Today Volume 24, Number 1 January 2019 REVIEWS Antithrombotic P2Y12 receptor POST SCREEN antagonists: recent developments in drug discovery Reviews 1 2 Younis Baqi and Christa E. Müller 1 Department of Chemistry, Faculty of Science, Sultan Qaboos University, PO Box 36, Postal Code 123, Muscat, Oman 2 Pharma-Center Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, An der Immenburg 4, D-53121 Bonn, Germany The P2Y12 receptor is one of eight known P2Y receptor subtypes, and belongs to the G-protein-coupled receptor (GPCR) family. The P2Y12 receptor is highly expressed on blood platelets and in the brain. Potent, selective, peripherally acting antagonists for the P2Y12 receptor are used clinically as antithrombotic drugs. Several different scaffolds have been identified as P2Y12 receptor antagonists, including irreversibly acting thienotetrahydropyridines (prodrugs), and reversible competitive antagonists, including adenine nucleotide analogs, piperazinyl-glutamate-quinolines, -pyridines, and -pyrimidines, and anthraquinone derivatives. Here, we provide an overview of the different scaffolds that have been developed as P2Y12 receptor antagonists, some of which have become important therapeutics. Introduction drugs have been found to be useful in reducing the risk of heart Cardiovascular diseases have been the leading cause of death attack and stroke [7,8]. and disability globally for the past 15 years, accounting for Ticlopidine (4), a predecessor of clopidogrel (1), was discovered 30% of all deaths [1,2]. In industrialized countries in particu- in 1972 to have antiplatelet aggregation properties in vivo and, a lar, this increase is thought to be the result mainly of unhealthy few years later, it was marketed in France for those at high risk for lifestyles [1–3]. ischemic heart disease and stroke [9], without its target being Platelets have a fundamental role in the formation and stabili- known. In 1991, it was also approved for the US market [10]. A zation of cardiovascular thrombosis [4]. They adhere to the sub- decade later, in 2001, the P2Y12 receptor was cloned and identified endothelial matrix following endothelial damage as a result of a as the target of ticlopidine and clopidogrel [11]. ADP is the ruptured atherosclerotic plaque, and then aggregate to form a endogenous agonist of the P2Y12 receptor, whereas ATP blocks prothrombotic surface that promotes clot formation and subse- the receptor [12] (for structures see Figs 1 and 2). quently vascular occlusion [5]. The activation step involves a series P2Y12 receptors show a restricted distribution, they are of reactions, including interaction with, and release of, several expressed in platelets [13] and in the central nervous system platelet-activating agonists, such as ADP, thrombin, and throm- (CNS), mainly in microglial cells [14], making it an ideal drug boxane A2 [5,6]. As a result, therapies that influence platelet target. The P2Y12 receptor belongs to the family of purine/pyrimi- functions are considered useful for the prevention and treatment dine nucleotide-activated P2Y receptors, which are class A, rho- of heart diseases associated with thrombus formation [e.g. acute dopsin-like GPCRs [15]. They belong to the d-branch of class A coronary syndrome (ACS)]. Currently, the standard therapeutics GPCRs, which additionally comprises receptors activated by lipids 1 for ACS are antiplatelet agents, such as clopidogrel ( , P2Y12 or peptides, as well as many orphan receptors, the cognate agonists 2 antagonist) or prasugrel ( , P2Y12 antagonist), often in combina- of which are still unknown or unconfirmed [16]. 3 tion with acetylsalicylic acid ( , aspirin, COX-1 inhibitor). These The P2Y12 receptor represents a successful drug target, with several clinical drugs on the market, including clopidogrel (1), prasugrel (2), ticlopidine (4), cangrelor (5), and ticagrelor (6), and more drugs in clinical trials [17,18]; for structures, see Fig. 1. Corresponding author: Baqi, Y. ([email protected]) 1359-6446/ã 2018 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.drudis.2018.09.021 www.drugdiscoverytoday.com 325 REVIEWS Drug Discovery Today Volume 24, Number 1 January 2019 Active Metabolites 1, Clopidogrel (IC50 155 nM) Reviews POST SCREEN O O 3, Acetylsalicylic acid 2, Prasugrel R138727 (ASA, Aspirin) (IC50 800 nM) 4, Ticlopidine (IC50 2000 nM) 5, Cangrelor 6, Ticagrelor (IC50 0.4 nm) (Ki 2.0 nm) Drug Discovery Today FIGURE 1 Chemical structures of marketed anticoagulant agents and their active metabolites with P2Y12 receptor-antagonistic activity, and of the cyclooxygenase (COX) inhibitor aspirin. Therefore, the development of P2Y12 antagonists has been an X-ray structures of the P2Y12 receptor active area of drug development, and efforts have been based on Crystal structures of the human P2Y12 receptor have recently various chemical scaffolds, including (i) thienotetrahydropyri- been resolved (Fig. 3). Structures of the receptor in a complex dines; (ii) adenine nucleotides and analogs; (iii) piperazinyl-gluta- with the agonists 2-methylthio-adenosine diphosphate (2MeS- mate-pyridines, -pyrimidines, and -quinolones; (iv) ADP, 7, Fig. 3a) and 2-methylthio-adenosine triphosphate anthraquinones; and (v) various other scaffolds, with the aim to (2MeS-ATP, 8, Fig. 3b) [24], and with the non-nucleotide antag- obtain new anticoagulant (antiplatelet) drugs. onist ethyl 6-(4-[(benzylsulfonyl)carbamoyl]piperidin-1-yl)-5- cyano-2-methylnicotinate (AZD1283, 9, Fig. 3c) [25] were Platelet aggregation obtained. These represent the first crystallographic determina- Platelet aggregation involves three different purinergic P2 recep- tions of a receptor of the d-branch of class A GPCRs in both tors, namely the ATP-gated ion channel receptor P2X1 and two agonist- and antagonist-bound states. The crystal structures purinergic GPCRs, P2Y1 and P2Y12, which are both activated by showed that the agonists and the non-nucleotide competitive ADP [19]. Thus, the extracellular concentration of ADP has a antagonist adopt different orientations in the P2Y12 receptor, crucial role in the process of platelet aggregation [20]. The P2X1 with a partial overlap in the orthosteric binding pockets (Fig. 2a- 2+ + + receptor, a cation channel (for Ca , Na and K ), mediates changes –c) [24,25]. Whereas the agonists lead to a contraction of the in platelet shape, the Gq-coupled P2Y1 receptor induces a transient binding site, the antagonist has the opposite effect, and its rise in intracellular calcium ion concentration, platelet shape binding pocket appears to be open and flexible. A crystal struc- change, and the initial, easily reversible platelet aggregation, ture of the P2Y12 receptor bound to an irreversible allosteric whereas the Gi-coupled P2Y12 receptor mediates progressive and antagonist would be of interest, but has not yet been published. persistent platelet aggregation (Fig. 2) [21–23]. Mutagenesis studies and the fact that the reaction of the purified 326 www.drugdiscoverytoday.com Drug Discovery Today Volume 24, Number 1 January 2019 REVIEWS Adenosine triphosphate Adenosine diphosphate (ATP) (ADP) Platelet shape Platelet shape Persistent change, and change and platelet platelet reversible LGIC aggregation activation platelet Amplifies GPCRs aggregation intracellular Ca2+ Fast and short Increase in Decrease in Ca2+ influx into intracellular intracellular POST SCREEN platelets P2X1 Ca2+ P2Y1 P2Y12 cAMP Antagonists Antagonists Na+ G G Well-established Reviews potentially have potentially have q/11 i/o clinical drug antithrombotic antithrombotic 2+ target for Ca2+ effects Ca effects cAMP antithrombotic activity Drug Discovery Today FIGURE 2 Prothrombotic activity of ATP-gated ion channel P2X1 and ADP-activated P2Y1 and P2Y12 receptors. (a) (b) (c) 7, 2MeS-ADP 8, 2MeS-ATP 9, AZD1283 N ECL2 N ECL2 2MeSATP ECL3 2MeSADP ECL3 ECL1 AZD1283 III III IV II IV VI VII II I VI VII I V V C C Drug Discovery Today FIGURE 3 Cartoon representation of the crystal structures of the human P2Y12 receptor in complex with: (a) the full agonist 2MeS-ADP (7); (b) the partial agonist 2MeS-ATP (8), and (c) the competitive antagonist AZD1283 (9) [24,25]. www.drugdiscoverytoday.com 327 REVIEWS Drug Discovery Today Volume 24, Number 1 January 2019 16 18 P2Y12 receptor with the prasugrel metabolite led to stabilization highly unstable sulfenic acid ( ) or the thiol ( ), which are of the C175A mutant, but not of the C97A mutant, led to the believed to covalently bind to the receptor protein, forming a conclusion that cysteine 97 is the most likely reaction partner disulfide bond (19); thus, they act as covalent, allosteric antago- for the active metabolites of the thienotetrahydropyridine deri- nists at P2Y12 receptors (Fig. 5) [28,29]. vatives forming a disulfide bond. This cysteine residue does not Hepatic esterases hydrolyze the ester function in clopidogrel, form a disulfide bond in the X-ray structure; and is located in the generating the inactive metabolites 12 and 14. As a result, <10% upper part of transmembrane helix 3, not far from the orthos- of the absorbed clopidogrel is converted into the active metabo- teric ligand-binding site [20]. lites 16 and 18 in the liver (Fig. 5) [30–34]. Reviews Despite the success of the first generation of thienotetrahydro- Thienotetrahydropyridines: prodrugs of irreversible pyridines in reducing an array of thrombotic events, their slow POST SCREEN allosteric P2Y12 receptor antagonists onset of action (up to several days) because of the required metab- The basic
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