Novel P2Y12 adenosine diphosphate receptor antagonists for inhibition of platelet aggregation (II): Pharmacodynamic and pharmacokinetic characterization

Post, Joseph; Alexander, S P H; Wang, Yixin; Vincelette, Jon; Vergona, Ronald; Kent, L; Bryant, Judi; Sullivan, M.; Dole, William P.; Morser, John; Subramanyam, Babu

doi:10.1016/j.thromres.2008.04.009

Cited by 26 publications

(18 citation statements)

References 20 publications

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“…In-vitro, ADP-induced aggregation is potently inhibited by BX 667. Additionally, administration of BX 667 results in a rapid and sustained inhibition aggregation 35. This observation is also supported by the intravenous BX 048 and oral BX 667 administration in rat arteriovenous-shunt model which showed a similar pharmacodynamic relationship between the plasma concentration of BX 048 and thrombus inhibition 34.…”

Section: P2y Receptor Antagonistssupporting

confidence: 55%

Newer agents in antiplatelet therapy: a review

Yeung¹,

Holinstat²

2012

JBM

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Antiplatelet therapy remains the mainstay in preventing aberrant platelet activation in pathophysiological conditions such as myocardial infarction, ischemia, and stroke. Although there has been significant advancement in antiplatelet therapeutic approaches, aspirin still remains the gold standard treatment in the clinical setting. Limitations in safety, efficacy, and tolerability have precluded many of the antiplatelet inhibitors from use in patients. Unforeseen incidences of increased bleeding risk and recurrent arterial thrombosis observed in patients have hampered the development of superior next generation antiplatelet therapies. The pharmacokinetic and pharmacodynamic profiles have also limited the effectiveness of a number of antiplatelet inhibitors currently in use due to variability in metabolism, time to onset, and reversibility. A focused effort in the development of newer antiplatelet therapies to address some of these shortcomings has resulted in a significant number of potential antiplatelet drugs which target enzymes (phosphodiesterase, cyclooxygenase), receptors (purinergic, prostaglandins, protease-activated receptors, thromboxane), and glycoproteins (αIIbβ3, GPVI, vWF, GPIb) in the platelet. The validation and search for newer antiplatelet therapeutic approaches proven to be superior to aspirin is still ongoing and should yield a better pharmacodynamic profile with fewer untoward side-effects to what is currently in use today.

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Section: P2y Receptor Antagonistssupporting

confidence: 55%

Newer agents in antiplatelet therapy: a review

Yeung¹,

Holinstat²

2012

JBM

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“…Such compounds have been developed through the molecular optimization of quinoline derivatives (such as (S)-4-({[4-(1-carboxy-1-methylethoxy)-7-methylquinolin-2-yl]carbonyl}amino)-5-[4-(ethoxycarbonyl)piperazin-1-yl]-5-oxopentanoic acid, BX048, structure not shown) [57]. …”

Section: Resultsmentioning

confidence: 99%

Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information

Paoletta

Sabbadin

Kügelgen

et al. 2015

J Comput Aided Mol Des

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Summary The G protein-coupled P2Y12 receptor (P2Y12R) is an important antithrombotic target and of great interest for pharmaceutical discovery. Its recently solved, highly divergent crystallographic structures in complex either with nucleotides (full or partial agonist) or with a nonnucleotide antagonist raise the question of which structure is more useful to understand ligand recognition. Therefore, we performed extensive molecular modeling studies based on these structures and mutagenesis, to predict the binding modes of major classes of P2Y12R ligands previously reported. Various nucleotide derivatives docked readily to the agonist-bound P2Y12R, but uncharged nucleotide-like antagonist ticagrelor required a hybrid receptor resembling the agonist-bound P2Y12R except for the top portion of TM6. Supervised molecular dynamics (SuMD) of ticagrelor binding indicated interactions with the extracellular regions of P2Y12R, defining possible meta-binding sites. Ureas, sulfonylureas, sulfonamides, anthraquinones and glutamic acid piperazines docked readily to the antagonist-bound P2Y12R. Docking dinucleotides at both agonist- and antagonist-bound structures suggested interactions with two P2Y12R pockets. Thus, our structure-based approach consistently rationalized the main structure-activity relationships within each ligand class, giving useful information for designing improved ligands.

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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%

“…, 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 (Post et al. , 2008).…”

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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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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Novel P2Y12 adenosine diphosphate receptor antagonists for inhibition of platelet aggregation (II): Pharmacodynamic and pharmacokinetic characterization

Cited by 26 publications

References 20 publications

Newer agents in antiplatelet therapy: a review

Newer agents in antiplatelet therapy: a review

Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information

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

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