Novel P2Y12 adenosine diphosphate receptor antagonists for inhibition of platelet aggregation (I): In vitro effects on platelets

Bryant, Judi; Post, Joseph; Alexander, S P H; Wang, Yixin; Kent, L; Schirm, Sabine; Tseng, Jih-Lie; Subramanyam, Babu; Buckman, Brad O.; Islam, Imadul; Shuanggui, Yuan; Sullivan, M.; Snider, Mike; Morser, John

doi:10.1016/j.thromres.2008.03.026

Cited by 26 publications

(15 citation statements)

References 32 publications

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“…Preclinical studies. BX 667 is metabolized by esterases to the carboxylic acid form, BX 048, without a significant change in binding affinity and platelet inhibitory potency [inhibitory concentration 50% (IC50) = 97 nM, IC50 = 290 nM respectively] (Wang et al, 2007;Bryant et al, 2008;Post et al, 2008). Administration of BX 667 results in a rapid and sustained inhibition of platelet aggregation where the extent and duration of platelet inhibition is directly proportional to circulating plasma levels .…”

Section: Elinogrel (Prt060128)mentioning

confidence: 99%

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Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases

Siller‐Matula

Krumphuber

Jilma

2010

British J Pharmacology

100

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Platelet inhibitors are the mainstay treatment for patients with vascular diseases. The current 'gold standard' antiplatelet agent clopidogrel has several pharmacological and clinical limitations that have prompted the search for more effective platelet antagonists. The candidates include various blockers of the purinergic P2Y12 receptor such as prasugrel, an oral irreversible thienopyridine; two adenosine triphosphate analogues that bind reversibly to the P2Y12 receptor: ticagrelor (oral) and cangrelor (intravenous); elinogrel, a direct-acting reversible P2Y12 receptor inhibitor (the only antiplatelet compound that can be administered both intravenously and orally); BX 667, an orally active and reversible small-molecule P2Y12 receptor antagonist; SCH 530348, SCH 205831, SCH 602539 and E5555, highly selective and orally active antagonists on the protease-activated receptor 1. A number of drugs also hit new targets: terutroban, an oral, selective and specific inhibitor of the thromboxane receptor; ARC1779, a second-generation, nuclease resistant aptamer which inhibits von Willebrand factordependent platelet aggregation; ALX-0081, a bivalent humanized nanobody targeting the GPIb binding site of von Willebrand factor and AJW200, an IgG4 monoclonal antibody of von Willebrand factor. The pharmacology and clinical profiles of new platelet antagonists indicate that they provide more consistent, more rapid and more potent platelet inhibition than agents currently used. Whether these potential advantages will translate into clinical advantages will require additional comparisons in properly powered, randomized, controlled trials.

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Section: Elinogrel (Prt060128)mentioning

confidence: 99%

“…BX 667 is metabolized by esterases to the carboxylic acid form, BX 048, without a significant change in binding affinity and platelet inhibitory potency [inhibitory concentration 50% (IC50) = 97 nM, IC50 = 290 nM respectively] (Wang et al. , 2007; Bryant et al. , 2008; Post et al.…”

mentioning

confidence: 99%

Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases

Siller‐Matula

Krumphuber

Jilma

2010

British J Pharmacology

100

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“…Although a large number of MCH 1 receptor antagonists have already been identified by various pharmaceutical companies, this is the first report, to our knowledge, that provides clear evidence of a compound that slowly dissociates from the receptor. Whereas some targets are reported to cause adverse side effects due to prolonged occupancy (Copeland et al ., ; Bryant et al ., ; Tummino and Copeland, ), it is thought that the unique property of MQ1 would be beneficial with respect to prolongation of pharmacodynamic efficacy in vivo .…”

Section: Discussionmentioning

confidence: 99%

The MCH₁ receptor, an anti‐obesity target, is allosterically inhibited by 8‐methylquinoline derivatives possessing subnanomolar binding and long residence times

Sakurai

Ogawa

Ishihara

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEMelanin-concentrating hormone receptor 1 (MCH1 receptor) antagonists are being considered as anti-obesity agents. The present study reports a new class of MCH1 receptor antagonists with an 8-methylquinoline scaffold. The molecular mechanism of MCH1 receptor blockade by these antagonists was examined. EXPERIMENTAL APPROACHThe pharmacological properties of the 8-methylquinolines as exemplified by MQ1 were evaluated by use of multiple biophysical and cell-based functional assays. KEY RESULTSMultiple signalling pathways for Gαi and Gαq, and β-arrestin were inhibited by MQ1. Furthermore, MQ1 produced an insurmountable antagonism, causing a rightward shift of the curve for concentration-dependent binding of MCH along with a progressive reduction of the maximal response. The dissociation kinetics for MQ1 were determined from washout experiments as well as by affinity selection-MS. In short, MQ1 was shown to be a slowly dissociating reversible MCH1 receptor blocker with a low Koff value. CONCLUSION AND IMPLICATIONSThis is the first time that a slowly dissociating negative allosteric modulator of the MCH1 receptor has been demonstrated to inhibit the numerous signalling pathways of this receptor. The characteristics of MQ1 are superior and distinct from previously reported MCH1 receptor antagonists, making members of this chemotype attractive as drug candidates. Abbreviations

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“…It is metabolized by esterases to form the equipotent carboxylic acid active metabolite BX 048. Oral administration of BX 667 or intravenous BX 048 to rats or dogs results in a rapid and sustained inhibition of platelet aggregation, where the extent and duration of platelet inhibition are directly proportional to circulating plasma levels of the compounds [Wang et al., ; Bryant et al., ; Post et al., ]. As no further development or trials have been reported for some time, this program may have been discontinued.…”

Section: P2y12 Receptor Antagonistsmentioning

confidence: 99%

Targeting Platelet G Protein‐Coupled Receptors for Antithrombotic Therapy

Fälker

Nazaré

Wonerow

et al. 2013

Drug Development Research

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Preclinical Research Platelets are small anucleated cells produced by bone marrow megakaryocytes that circulate in the blood as sentinels of vascular integrity. They play a pivotal role in the regulation of vascular homeostasis through adhesion to the injured vessel wall, aggregation, propagation of coagulation, and thrombus formation. Furthermore, platelets are also involved in fibrinolysis and the repair of the blood vessel wall, restoring blood flow and vascular integrity. Under pathophysiological conditions such as atherosclerosis, inappropriate platelet aggregation and clot formation can cause vascular occlusions, resulting in myocardial infarctions or stroke that, according to the World Health Organization, represent with more than 10% of worldwide death a major health risk (http://who.int/mediacentre/factsheets/fs310/en/). Over the last several decades, increasing efforts have been made to elucidate the cellular components, signaling pathways, and risk factors contributing to platelet activation with the main goal of providing a sound basis for the development of antiplatelet drugs and novel therapeutic treatment strategies. The family of seven transmembrane receptors, also designated G protein‐coupled receptors (GPCRs), represented by approximately 800 members identified in the human genome represent the largest class of receptors and, hence, the richest source of targets for drug discovery. Here, we here provide an overview of the commonly applied therapies targeting platelet‐GPCRs as well as a brief summary of novel approaches.

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Novel P2Y12 adenosine diphosphate receptor antagonists for inhibition of platelet aggregation (I): In vitro effects on platelets

Cited by 26 publications

References 32 publications

Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases

Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases

The MCH₁ receptor, an anti‐obesity target, is allosterically inhibited by 8‐methylquinoline derivatives possessing subnanomolar binding and long residence times

Targeting Platelet G Protein‐Coupled Receptors for Antithrombotic Therapy

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Novel P2Y12 adenosine diphosphate receptor antagonists for inhibition of platelet aggregation (I): In vitro effects on platelets

Cited by 26 publications

References 32 publications

Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases

Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases

The MCH1 receptor, an anti‐obesity target, is allosterically inhibited by 8‐methylquinoline derivatives possessing subnanomolar binding and long residence times

Targeting Platelet G Protein‐Coupled Receptors for Antithrombotic Therapy

Contact Info

Product

Resources

About

The MCH₁ receptor, an anti‐obesity target, is allosterically inhibited by 8‐methylquinoline derivatives possessing subnanomolar binding and long residence times