Preclinical and Clinical Studies with Selective Reversible Direct P2Y<sub>12</sub>Antagonists

Giezen, J.J.J. van; Humphries, Robert G.

doi:10.1055/s-2005-869525

Cited by 244 publications

(153 citation statements)

References 44 publications

Supporting

Mentioning

144

Contrasting

Unclassified

Order By: Relevance

“…In fact, P2Y 12 inhibition could amplify the antiplatelet effect of prostacyclin (PGI 2 ) and other inhibitory prostaglandins, which increase the platelet levels of cyclic adenosine monophosphate (cyclic AMP), a potent inhibitor of PA, by stimulating AC [19]. To test our hypothesis, we measured the effects of increasing concentrations of PGI 2 on PA and secretion of washed, normal human platelets induced by thrombin in the presence or absence of saturating concentrations of the specific antagonist of P2Y 12 , ARC69931MX [20] or the specific antagonist of P2Y 1 , MRS2500 [21,22].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin

Cattaneo

Lecchi

2007

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Summary. Background: Activation of two receptors for adenosine diphosphate (ADP), P2Y 1 and P2Y 12 , is necessary for ADP-induced platelet aggregation (PA). It is generally believed that the antithrombotic effects of drugs inhibiting P2Y 12 , such as clopidogrel, are uniquely mediated by inhibition of P2Y 12 -dependent PA. However, as P2Y 12 is negatively coupled to adenylyl cyclase (AC), its inhibition may also exert antithrombotic effects through the potentiation of prostacyclin (PGI 2 ), which inhibit PA by stimulating AC. Objectives: To test whether inhibition of P2Y 12 potentiates the antiplatelet effects of PGI 2 . Methods: We measured the effects of PGI 2 (0.01-10 lM) on PA of washed human platelets induced by thrombin (0.5 U mL )1 ) in the presence or absence of ARC69931MX (anti-P2Y 12 ) or MRS2500 (anti-P2Y 1 ). Results: PGI 2 inhibited PA in the presence of anti-P2Y 12 , but not in the presence of anti-P2Y 1 or in the absence of inhibitors. In contrast, dibutyrylcyclicAMP inhibited PA both in the presence and absence of anti-P2Y 1 or anti-P2Y 12 . PGI 2 increased platelet cyclicAMP levels only in the absence of thrombin or in the presence of thrombin plus anti-P2Y 12 . Conclusions: PGI 2 did not inhibit PA induced by thrombin, because its effect on AC was prevented by released ADP interacting with P2Y 12 . Anti-P2Y 12 drugs, by rescuing AC activity, potentiate the antiplatelet effect of PGI 2 , which may contribute to their antithrombotic effect.

show abstract

Section: Introductionmentioning

confidence: 99%

Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin

Cattaneo

Lecchi

2007

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…MRS2496 (with a binding K i at the human P2Y 1 receptor of 76 nM), by virtue of being a phosphonate rather than phosphate, is not subject to hydrolysis by nucleotidases. The nucleotide/nucleoside derivatives AR-C69931X, AZD6140, INS49266 and INS 50589 are selective P2Y 12 receptor antagonists that do not require metabolic activation in vivo (Ingall et al 1999, van Giezen & Humphries 2005, Douglas et al 2002.…”

Section: Use Of Ring Constraints To Define the Conformational Preferementioning

confidence: 99%

Agonists and Antagonists for P2 Receptors

Jacobson

Costanzi

Joshi

et al. 2006

Novartis Foundation Symposia

View full text Add to dashboard Cite

Recent work has identified nucleotide agonists selective for P2Y 1 , P2Y 2 and P2Y 6 receptors and nucleotide antagonists selective for P2Y 1 , P2Y 12 and P2X 1 receptors. Selective non-nucleotide antagonists have been reported for P2Y 1 , P2Y 2 , P2Y 6 , P2Y 12 , P2Y 13 , P2X 2/3 /P2X 3 and P2X 7 receptors. For example, the dinucleotide INS 37217 (Up 4 dC) potently activates the P2Y 2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X 2/3 /P2X 3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y 1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y 1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC 50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC 50 ) of 0.4 nM at the P2Y 1 receptor, with >10 000-fold selectivity in comparison to P2Y 12 and P2Y 13 receptors. At P2Y 6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. Extracellular purine and pyrimidine nucleotides act as neurotransmitters/modulators . These ubiquitous signalling molecules modulate the function of diverse mammalian cell types and tissues under both normal and pathophysiological conditions. Receptors for extracellular nucleotides have been characterized through medicinal chemical, molecular biological, and pharmacological approaches. The eight subtypes of P2Y receptors, denoted P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 and P2Y 14 , are all seven transmembrane-spanning (7TM) receptors, which couple to G proteins. The seven P2X receptor subunits (P2X 1 -P2X 7 ) form multimeric ligand-gated ion channels. The distribution of P2Y receptors is broad, and the relevant therapeutic interests include antithrombotic therapy, modulation of the immune system and cardiovascular system, and treatment of cystic fibrosis and other pulmonary diseases (Yerxa et al 2002). Several of the

show abstract

“…The T max of ticagrelor is 1.3e2 h and plasma half life (t1/2) is 7e12 h. 15 It is metabolized in the liver by CYP3A4 enzyme to produce active metabolite AR-C124910XX. This metabolite is as potent as ticagrelor on P2Y 12 receptor and is present in the circulation at approximately 1/3 of the concentration of the parent drug.…”

Section: Ticagrelor: Pharmacological Aspectsmentioning

confidence: 99%

Ticagrelor: molecular discovery to clinical evidence

Sinha

2012

Indian Heart Journal

View full text Add to dashboard Cite

1.Acute coronary syndrome e global and Indian perspective Cardiovascular death (CVD) is one of the leading causes in the non-communicable disease (NCD) deaths. According to WHO estimates around 17 million people die of CVD each year, 1 out of which coronary heart disease (CHD) accounts for 7.1 million deaths. Developing countries like India are witnessing economic transition, urbanization and industrialization resulting in major lifestyle changes like increased tobacco use, physical inactivity and unhealthy diet, that has lead to a dramatic increase in CVD and CHD. 2 In Indian context, there are many challenges in managing patients of ACS. ACS patients in India die younger and sicker with average age at 57 years, almost 10e15 years younger than in west. Moreover, they carry high risk factor profile that includes Diabetes, Hypertension, Smoking and Dyslipidemia and close to 20% patients suffer from a 2nd heart attack in India. 3 As per CREATE registry 60% of patients in India were of STEMI whereas as per global registry data 40% patients were of STEMI. This implies that patients admitted to Indian hospitals with acute coronary syndromes are likely to have a worse prognosis than those in developed countries. In spite of being at high risk, in India, <10% ACS patients are managed through PCI with less than 15% receiving DAPT. 3 Experience in the developed world has shown that significant reductions in CAD prevalence and mortality can be

show abstract

Preclinical and Clinical Studies with Selective Reversible Direct P2Y₁₂Antagonists

Cited by 244 publications

References 44 publications

Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin

Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin

Agonists and Antagonists for P2 Receptors

Ticagrelor: molecular discovery to clinical evidence

Contact Info

Product

Resources

About

Preclinical and Clinical Studies with Selective Reversible Direct P2Y12Antagonists

Cited by 244 publications

References 44 publications

Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin

Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin

Agonists and Antagonists for P2 Receptors

Ticagrelor: molecular discovery to clinical evidence

Contact Info

Product

Resources

About

Preclinical and Clinical Studies with Selective Reversible Direct P2Y₁₂Antagonists