Challenges in Design and Development of PAR Inhibitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-45-SCI-45
Author(s):  
Patricia Andrade-Gordon
Keyword(s):  
Drug Target ◽  
Human Platelet ◽  
Bleeding Risk ◽  
G Protein Coupled Receptors ◽  
Protease Activated Receptors ◽  
Small Molecule Antagonist ◽  
Clinical Benefits ◽  
Platelet Aggregates ◽  
G Protein Coupled ◽  
Sustained Activation

Abstract Abstract SCI-45 Inappropriate and sustained activation of platelets is a major cause of vascular occlusive diseases such as angina, myocardial infarction, and stroke. The development of thrombi within blood vessels results from the formation of platelet aggregates and fibrin deposits, and heavily depends on the actions of α-thrombin. It is now well recognized that human platelet responses to α-thrombin are mediated by the protease-activated receptors PAR1 and PAR4. Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G-protein-coupled receptors, which are enzymatically cleaved to expose a new extracellular N-terminus that acts as a “tethered” activating ligand. Since the discovery of PAR1 as the major contributor to human platelet aggregation, there has been a keen interest to develop antagonist as potential antithrombotics. However, there have been many issues and challenges in this endeavor. One crucial challenge to the discovery of potent antagonists is the strong entropy advantage offered by the intramolecular binding mechanism of PARs activation, which presents a great disadvantage to a circulating small molecule antagonist. To be an effective therapeutic agent, a PAR1 antagonist not only should bind tightly to the receptor but also possess suitable binding kinetics. Another issue for the discovery of PAR1 antagonists is the preclinical logistics associated with species variability of PAR1 on platelets. Despite these challenges, PAR1 has been an attractive drug target and there has been considerable activity and progress in the discovery and development of PAR1 antagonist as therapeutic agents. The promise of these novel therapeutics is reflected by two antiplatelet PAR1 antagonists in advanced clinical trials. The clinical benefits derived from these agents will be determined by the tight balance between delivering efficacy in the context of thrombotic disease and controlling the bleeding risk. The discussion will focus on the challenges from discovery to development of these great potential opportunities in the prevention of atherothrombotic disease. Disclosures: Andrade-Gordon: Johnson & Johnson: Employment.

Current Status in the Design and Development of Agonists and Antagonists of Adenosine A3 Receptor as Potential Therapeutic Agents

2019 ◽  
Vol 25 (25) ◽  
pp. 2772-2787 ◽  
Author(s):  
Raghu P. Mailavaram ◽  
Omar H.A. Al-Attraqchi ◽  
Supratik Kar ◽  
Shinjita Ghosh
Keyword(s):  
Drug Target ◽  
Therapeutic Agents ◽  
G Protein Coupled Receptors ◽  
Current Status ◽  
Renal Diseases ◽  
Adenosine A3 Receptor ◽  
Drug Candidates ◽  
Novel Drugs ◽  
The Family ◽  
G Protein Coupled

Adenosine receptors (ARs) belongs to the family of G-protein coupled receptors (GPCR) that are responsible for the modulation of a wide variety of physiological functions. The ARs are also implicated in many diseases such as cancer, arthritis, cardiovascular and renal diseases. The adenosine A3 receptor (A3AR) has emerged as a potential drug target for the progress of new and effective therapeutic agents for the treatment of various pathological conditions. This receptor’s involvement in many diseases and its validity as a target has been established by many studies. Both agonists and antagonists of A3AR have been extensively investigated in the last decade with the goal of developing novel drugs for treating diseases related to immune disorders, inflammation, cancer, and others. In this review, we shall focus on the medicinal chemistry of A3AR ligands, exploring the diverse chemical classes that have been projected as future leading drug candidates. Also, the recent advances in the therapeuetic applications of A3AR ligands are highlighted.

Drug-Target Residence Time-A Case for G Protein-Coupled Receptors

2014 ◽  
Vol 34 (4) ◽  
pp. 856-892 ◽  
Author(s):  
Dong Guo ◽  
Julia M. Hillger ◽  
Adriaan P. IJzerman ◽  
Laura H. Heitman
Keyword(s):  
G Protein ◽  
Residence Time ◽  
Drug Target ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis

Blood ◽  
2009 ◽  
Vol 113 (20) ◽  
pp. 4942-4954 ◽  
Author(s):  
Yotis A. Senis ◽  
Michael G. Tomlinson ◽  
Stuart Ellison ◽  
Alexandra Mazharian ◽  
Jenson Lim ◽  
...  
Keyword(s):  
G Protein ◽  
Platelet Activation ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Underlying Mechanism ◽  
G Protein Coupled Receptors ◽  
Bleeding Tendency ◽  
Platelet Surface ◽  
Surface Receptors ◽  
G Protein Coupled

Abstract Platelets play a fundamental role in hemostasis and thrombosis. They are also involved in pathologic conditions resulting from blocked blood vessels, including myocardial infarction and ischemic stroke. Platelet adhesion, activation, and aggregation at sites of vascular injury are regulated by a diverse repertoire of tyrosine kinase–linked and G protein–coupled receptors. Src family kinases (SFKs) play a central role in initiating and propagating signaling from several platelet surface receptors; however, the underlying mechanism of how SFK activity is regulated in platelets remains unclear. CD148 is the only receptor-like protein tyrosine phosphatase identified in platelets to date. In the present study, we show that mutant mice lacking CD148 exhibited a bleeding tendency and defective arterial thrombosis. Basal SFK activity was found to be markedly reduced in CD148-deficient platelets, resulting in a global hyporesponsiveness to agonists that signal through SFKs, including collagen and fibrinogen. G protein–coupled receptor responses to thrombin and other agonists were also marginally reduced. These results highlight CD148 as a global regulator of platelet activation and a novel antithrombotic drug target.

scholarly journals Evaluation on Potential Contributions of Protease Activated Receptors Related Mediators in Allergic Inflammation

2014 ◽  
Vol 2014 ◽  
pp. 1-20 ◽  
Author(s):  
Huiyun Zhang ◽  
Xiaoning Zeng ◽  
Shaoheng He
Keyword(s):  
Serine Proteases ◽  
Inflammatory Cell ◽  
Allergic Inflammation ◽  
G Protein Coupled Receptors ◽  
Cell Behavior ◽  
Protease Activated Receptors ◽  
Pathologic Process ◽  
Allergic Disorders ◽  
G Protein Coupled

Protease activated receptors (PARs) have been recognized as a distinctive four-member family of seven transmembrane G protein-coupled receptors (GPCRs) that can be cleaved by certain serine proteases. In recent years, there has been considerable interest in the role of PARs in allergic inflammation, the fundamental pathologic changes of allergy, but the potential roles of PARs in allergy remain obscure. Since many of these proteases are produced and actively involved in the pathologic process of inflammation including exudation of plasma components, inflammatory cell infiltration, and tissue damage and repair, PARs appear to make important contribution to allergy. The aim of the present review is to summarize the expression of PARs in inflammatory and structural cells, the influence of agonists or antagonists of PARs on cell behavior, and the involvement of PARs in allergic disorders, which will help us to better understand the roles of serine proteases and PARs in allergy.

Continuous signaling via PI3K isoforms β and γ is required for platelet ADP receptor function in dynamic thrombus stabilization

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 3045-3052 ◽  
Author(s):  
Judith M. E. M. Cosemans ◽  
Imke C. A. Munnix ◽  
Reinhard Wetzker ◽  
Regine Heller ◽  
Shaun P. Jackson ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
G Protein Coupled Receptors ◽  
Platelet Aggregate ◽  
Platelet Aggregates ◽  
Adp Receptor ◽  
Phosphoinositide 3 Kinase ◽  
Novel Concept ◽  
Induced Aggregation ◽  
G Protein Coupled ◽  
Intrinsic Dynamic

Abstract Signaling from collagen and G protein–coupled receptors leads to platelet adhesion and subsequent thrombus formation. Paracrine agonists such as ADP, thromboxane, and Gas6 are required for platelet aggregate formation. We hypothesized that thrombi are intrinsically unstable structures and that their stabilization requires persistent paracrine activity and continuous signaling, maintaining integrin αIIbβ3 activation. Here, we studied the disassembly of human and murine thrombi formed on collagen under high shear conditions. Platelet aggregates rapidly disintegrated (1) in the absence of fibrinogen-containing plasma; (2) by blocking or inhibiting αIIbβ3; (3) by blocking P2Y12 receptors; (4) by suppression of phosphoinositide 3-kinase (PI3K) β. In murine blood, absence of PI3Kγ led to formation of unstable thrombi, leading to dissociation of multiplatelet aggregates. In addition, blocking PI3Kβ delayed initial thrombus formation and reduced individual platelet-platelet contact. Similarly without flow, agonist-induced aggregation was reversed by late suppression of P2Y12 or PI3K isoforms, resulting in single platelets that had inactivated αIIbβ3 and no longer bound fibrinogen. Together, the data indicate that continuous outside-in signaling via P2Y12 and both PI3Kβ and PI3Kγ isoforms is required for perpetuated αIIbβ3 activation and maintenance of a platelet aggregate. This novel concept of intrinsic, dynamic thrombus instability gives possibilities for the use of antiplatelet therapy.

scholarly journals Protease Activated Receptors and Arthritis

2021 ◽  
Vol 22 (17) ◽  
pp. 9352
Author(s):  
Flora Lucena ◽  
Jason J. McDougall
Keyword(s):  
Serine Proteases ◽  
Vascular Reactivity ◽  
Structural Integrity ◽  
Therapeutic Potential ◽  
G Protein Coupled Receptors ◽  
Tissue Remodelling ◽  
Protease Activated Receptors ◽  
Tethered Ligand ◽  
Arthritic Joints ◽  
G Protein Coupled

The catabolic and destructive activity of serine proteases in arthritic joints is well known; however, these enzymes can also signal pain and inflammation in joints. For example, thrombin, trypsin, tryptase, and neutrophil elastase cleave the extracellular N-terminus of a family of G protein-coupled receptors and the remaining tethered ligand sequence then binds to the same receptor to initiate a series of molecular signalling processes. These protease activated receptors (PARs) pervade multiple tissues and cells throughout joints where they have the potential to regulate joint homeostasis. Overall, joint PARs contribute to pain, inflammation, and structural integrity by altering vascular reactivity, nociceptor sensitivity, and tissue remodelling. This review highlights the therapeutic potential of targeting PARs to alleviate the pain and destructive nature of elevated proteases in various arthritic conditions.

A combination of pharmacophore modeling, molecular docking, and virtual screening for P2Y12 receptor antagonists from Chinese herbs

2015 ◽  
Vol 93 (3) ◽  
pp. 311-316 ◽  
Author(s):  
Yusu He ◽  
Ludi Jiang ◽  
Zhen Yang ◽  
Yanjiang Qiao ◽  
Yanling Zhang
Keyword(s):  
Drug Target ◽  
Thrombus Formation ◽  
Pharmacophore Modeling ◽  
G Protein Coupled Receptors ◽  
Chinese Herbs ◽  
Receptor Antagonists ◽  
Hydrogen Bond Acceptor ◽  
Reliable Source ◽  
G Protein Coupled ◽  
Pharmacophore Models

P2Y12, a member of the G-protein-coupled receptors, is associated with abnormal platelet aggregation, a condition that contributes to thrombus formation. As receptor antagonists are effective solutions for anti-thrombus, the P2Y12 receptor is a popular drug target. After the recent resolution of the P2Y12 receptor’s crystal structure, pharmacophore modeling and docking were combined to discover potential natural antagonists. Various approaches were used for the validation of the pharmacophore models and the optimization of docking algorithms. Hypo18, which was generated by 24 known antagonists, was determined to be the best hypothesis and is comprised of one ring aromatic, one hydrogen bond acceptor, one exclude volume, and three hydrophobic features. Hypo18 was thus utilized to screen TCMD (version 2009) to identify any potential active compounds, which then resulted in a hit list of 121 compounds with drug-likeness analysis. In addition, docking was used to refine the pharmacophore-based screening results as a cross-linking method. Then, the top 20 compounds with high docking scores were reserved. This paper provides a reliable source for discovering natural P2Y12 receptor antagonists from traditional Chinese herbs.

scholarly journals The potential of different Autotaxin inhibitor types regulating catalysis-dependent and -independent signalling

2019 ◽  
Author(s):  
Fernando Salgado Polo ◽  
Anastassis Perrakis
Keyword(s):  
Drug Target ◽  
Cellular Responses ◽  
Binding Mode ◽  
G Protein Coupled Receptors ◽  
Allosteric Site ◽  
Physiological Processes ◽  
Independent Functions ◽  
G Protein Coupled ◽  
Mediated Catalysis ◽  
Important Drug

Autotaxin (ATX) is a secreted lysophospholipase D, catalysing the conversion of lysophosphatidylcholine (LPC) to bioactive lysophosphatidic acid (LPA). LPA acts through two families of G protein-coupled receptors (GPCRs) controlling key cellular responses, and is implicated in many physiological processes and pathologies. ATX has therefore been established as an important drug target in the pharmaceutical industry. Structural and biochemical studies of ATX have shown that it has a bimetallic nucleophilic catalytic site, a substrate-binding (orthosteric) hydrophobic pocket that accommodates the lipid alkyl chain, and an allosteric tunnel that can accommodate various steroids and LPA. Here we first review what is known about ATX-mediated catalysis, crucially in light of allosteric regulation. We then present the known ATX catalysis-independent functions, including binding to cell-surface integrins and proteoglycans. In light of these data we then discuss the four types of ATX inhibitors, as classified depending on their binding to the orthosteric and/or the allosteric site. Finally, we analyse the binding mode of known members of all four types and discuss how mechanistic differences might differentially modulate the activity of the ATX-LPA signalling axis, and clinical applications including cancer.

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