Delving into the Latest Updates on Elinogrel potassium with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Elinogrel, Elinogrel potassium (USAN)

+ [5]

Target

P2Y12 receptor

Action

antagonists

Mechanism

P2Y12 receptor antagonists(Purinergic receptor P2Y12 antagonists)

Therapeutic Areas

Nervous System DiseasesCardiovascular DiseasesOther Diseases+ [1]

Active Indication-

Inactive Indication

Acute Coronary SyndromeAngina PectorisRenal Insufficiency+ [2]

Originator Organization

Novartis Pharma AG

Active Organization-

Inactive Organization

Novartis Pharma AG

Portola Pharmaceuticals LLC

Novartis AG

License Organization

Novartis AG

Portola Pharmaceuticals LLC

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC20H15ClFKN5O5S2

InChIKeyORAKJDGBKULZRH-UHFFFAOYSA-N

CAS Registry936501-01-8

View All Structures (2)

Selatogrel is a potent inhibitor of adenosine diphosphate (ADP) binding to the P2Y12 receptor, preventing platelet activation. We have previously shown that the P2Y12 receptor constitutively activates Gi- and Go-protein-mediated signaling in human platelets. Here, we report that selatogrel acts as an inverse agonist of the P2Y12 receptor. Specifically, using bioluminescence resonance energy transfer2 (BRET2) probes, selatogrel, ticagrelor, and elinogrel were shown to stabilize the inactive form of the G_αi/o-G_βγ complex in cells with recombinant expression of the P2Y12 receptor. In dose-response experiments, while selatogrel exhibited a maximal efficacy similar to ticagrelor, selatogrel was approximately 100-fold more potent than ticagrelor. Quantification of relative cyclic adenosine monophosphate (cAMP) levels in cells expressing the cAMP BRET1 sensor (CAMYEL probe) confirmed that selatogrel completely abolished the constitutive activity of the P2Y12 receptor. In agreement, selatogrel increased basal cAMP levels in human platelets, confirming inverse agonism on the endogenous human platelet P2Y12 receptor. In agreement with the biochemical phenotype of inverse agonism efficacy of selatogrel, the 2.8 Angstrom resolution cocrystal structure of selatogrel bound to the P2Y12 receptor confirmed that selatogrel stabilizes the inactive, basal state of the receptor. Selatogrel bound to pocket 1, spanning helix III to VII. Furthermore, the binding mode of selatogrel, suggesting steric overlap with the proposed binding site of ADP and the ADP analog 2-methylthioadenosine diphosphate (2MeSADP), agrees with the functional characterization of selatogrel preventing platelet activation by blocking ADP binding to the P2Y12 receptor.

02 Jan 2022·PlateletsQ3 · MEDICINE

The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration

Q3 · MEDICINE

Article

Author: Lack, Benoît ; Guillaumat, Isabelle ; Murphy, Mark J. ; Riederer, Markus A. ; Baumann, Martine

Here, we report the in vitro characterization of the P2Y12 receptor antagonist selatogrel (ACT-246475). Binding studies with radiolabeled selatogrel demonstrated that selatogrel is a competitive antagonist of ADP binding to the P2Y12 receptor with a fast onset of action. Consequently, selatogrel was confirmed to be a potent inhibitor of P2Y12-mediated intra-platelet signaling and ADP-induced platelet activation. Characterization of selatogrel in platelet-rich plasma in vitro demonstrated that the mode of anti-coagulation affected the anti-platelet potency. Specifically, in platelet-rich plasma containing physiological calcium concentration (anticoagulated with a direct thrombin inhibitor), selatogrel achieved half-maximal inhibition of ADP-induced platelet aggregation at a 3-fold lower concentration than in conditions with low calcium concentration (anticoagulated with citrate). Furthermore, calcium-dependent reduction in selatogrel potency was observed in whole blood platelet aggregation using the VerifyNow™ system with a 3.7-fold potency loss in low calcium conditions. A comparable potency loss was also observed with the reversible P2Y12 receptor antagonists ticagrelor, cangrelor and elinogrel. Furthermore, receptor-binding experiments using radiolabeled selatogrel confirmed a 3-fold lowering of selatogrel binding affinity to the P2Y12 receptor in low calcium conditions. In conclusion, our data suggest that in low calcium conditions (i.e., citrate-anticoagulated blood), there is a risk of underestimating the potency of reversible P2Y12 receptor antagonists. To avoid overdosing, and a potential increase in bleeding risk, we propose that the ex vivo evaluation of reversible P2Y12 receptor antagonists should be performed with platelet assay systems containing physiological calcium concentration.

30 Dec 2020·Current Pharmaceutical Design

Efficacy and Safety of Ticagrelor Compared to Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention: A Meta-Analysis

Article

Author: Shen, Su ; Wu, Haihong ; Xiang, Xiuying ; Li, Dandan ; Li, Xingang

Background:The Platelet Inhibition and Patient Outcomes (PLATO) study found that ticagrelor plus aspirin (TA) was more effective than clopidogrel plus aspirin (CA), without an increase in the risk of massive bleeding in patients undergoing percutaneous coronary intervention (PCI). Data from other studies indicate that the conclusion is controversial with the results obtained by PLATO.Aim:To investigate the efficacy and safety of TA, compared with CA, in patients with acute coronary syndrome (ACS) after PCI.Methods:A systematic literature search was performed in the MEDLINE, EMBASE, and Cochrane databases to compare the efficacy and safety of CA and TA treatment in patients with ACS after PCI. The endpoints were major adverse cardiac events (MACEs), death, stroke, myocardial infarction (MI), stent thrombosis, and bleeding events. The data analysis was performed using RevMan 5.3 software, and the odds ratios (ORs) and their 95% confidence intervals (CI) were calculated. The standards of reporting were in accordance with the PRISMA guidelines.Results:13 studies with a total of 58,062 patients were included in this study with a subgroup analysis of the European/American and Asian populations. In terms of effectiveness for MACEs, the European, American and Asian populations benefitted more from the TA treatment than the CA treatment (European and American populations, OR = 0.82, P = 0.0002; Asian, OR = 0.66, P<0.0001; total, OR = 0.78, P<0.0001). In terms of specific effectiveness indicators, such as stroke, MI, and stent thrombosis, the results of TA and CA groups in the European, American, and Asian populations were not consistent. In terms of safety, there was no statistical difference in total bleeding events between TA and CA treatments (OR = 1.19, P = 0.21). However, in the Asian population, the incidence of total bleeding events (OR = 1.52, P = 0.0004) in the TA group was higher than that in the CA group.Conclusion:The TA treatment in the European and American populations is more beneficial and safer than CA treatment. However, although the Asian population has this benefit, the risk of bleeding is significantly increased as well, and antiplatelet drugs should be chosen carefully.

100 Deals associated with Elinogrel potassium

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External Link

KEGG	Wiki	ATC	Drug Bank
D09608	Elinogrel potassium	-	DB06350

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Phase 2	Canada	Portola Pharmaceuticals LLC	01 Dec 2008
Thrombosis	Phase 2	United States	Portola Pharmaceuticals LLC	01 Dec 2008
Thrombosis	Phase 2	Germany	Portola Pharmaceuticals LLC	01 Dec 2008
Thrombosis	Phase 2	Austria	Portola Pharmaceuticals LLC	01 Dec 2008
Thrombosis	Phase 2	Poland	Portola Pharmaceuticals LLC	01 Dec 2008
ST Elevation Myocardial Infarction	Phase 2	Canada	Portola Pharmaceuticals LLC	01 Nov 2007
ST Elevation Myocardial Infarction	Phase 2	United States	Portola Pharmaceuticals LLC	01 Nov 2007
Acute Coronary Syndrome	Phase 2	Canada	Portola Pharmaceuticals LLC	-
Acute Coronary Syndrome	Phase 2	United States	Portola Pharmaceuticals LLC	-
Angina Pectoris	Phase 2	-	Novartis Pharma AG	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00751231 (INNOVATE-PCI, Pubmed \| Circ Cardiovasc Interv)	Phase 2	-	652	Elinogrel	(obknjjzreg) = shzzhvgzxo hhuomqltvp (wrgymnfdha ) View more	Negative	01 Jun 2012
				Clopidogrel	(obknjjzreg) = wnhgpgdpig hhuomqltvp (wrgymnfdha ) View more