Disease relevance of AR-C69931MX

• ADP contributes to thrombosis by activating platelets, and AR-C69931MX is a specific antagonist of this process acting at the P2T receptor [1].
• Safety profile and tolerability of intravenous AR-C69931MX, a new antiplatelet drug, in unstable angina pectoris and non-Q-wave myocardial infarction [2].
• OBJECTIVE: This study assessed the safety profile, tolerability, and plasma concentrations at steady state of intravenous AR-C69931MX in patients with unstable angina pectoris or non-Q-wave myocardial infarction (MI) [2].

High impact information on AR-C69931MX

• In contrast, ADP failed to cause Akt phosphorylation in platelets from mice treated with clopidogrel, and thrombin and AYPGKF induced minimal phosphorylation of Akt, which was not affected by AR-C69931MX in these platelets [3].
• However, ADP caused Akt phosphorylation in Galphaq- and P2Y1-deficient platelets, which was completely blocked by AR-C69931MX [3].
• Activation of Rap1B induced by clustering of FcgammaRIIA was totally suppressed by AR-C69931MX, a specific antagonist of the G(i)-coupled ADP receptor P2Y12, but was not affected by blockade of the G(q)-coupled receptor, P2Y1 [4].
• We also found a new important action of the antithrombotic agent AR-C69931MX as a strong activator of P2Y13-mediated HDL endocytosis [5].
• The effect on ERK1 was inhibited by AR-C69931MX, a P2Y12 and P2Y13 antagonist [6].

Chemical compound and disease context of AR-C69931MX

• CONCLUSIONS: As adjunctive therapy to aspirin and low-molecular-weight heparin in patients with unstable angina or non-Q-wave MI, intravenous AR-C69931MX was well tolerated, with no difference in the incidence of serious adverse events compared with placebo [2].

Biological context of AR-C69931MX

• Clopidogrel and AR-C69931MX suppressed ADP-induced platelet aggregation, P-selectin expression and platelet-leukocyte conjugate formation whereas aspirin had no inhibitory effect [7].
• Further modification of the structure produced compound 10l (AR-C69931MX) having an IC50 of 0.4 nM [8].
• Inhibition of thrombin-induced platelet activation (2 nM) with combinations of AR-C69931MX and the thrombin inhibitor melagatran did also result in a strong synergistic effect [9].
• Values for both the ex vivo platelet aggregation and the bleeding times returned to control values shortly after discontinuation of AR-C69931MX [10].

Anatomical context of AR-C69931MX

• In contrast, carotid artery blood flow in five of six AR-C69931MX-treated animals was maintained for the duration of the protocol [10].
• Blockade of the platelet P2Y12 receptor by AR-C69931MX sustains coronary artery recanalization and improves the myocardial tissue perfusion in a canine thrombosis model [11].

Associations of AR-C69931MX with other chemical compounds

• Rac activation by in wild-type platelets could be blocked by chelation of intracellular Ca(2+) and was partially sensitive to apyrase and AR-C69931MX, an antagonist of the G(i)-coupled ADP receptor [12].
• The inhibition of U46619-induced ERK2 activation and platelet aggregation by AR-C69931MX are also rescued by epinephrine [13].
• The collagen-induced ERK2 activation was inhibited by indomethacin (88%) and by AR-C69931MX (70%), a specific antagonist of P2Y12, a Gi-coupled ADP receptor [14].
• Inhibition patterns by various combinations of AR-C69931MX, AdoPPS, and wortmannin suggested that P2Y1 and P2Y12 mediate alpha2beta1 activation through different pathways, with possible involvement of phosphoinositide 3-kinase in both [15].
• Heparin-coated stents were used in the third experiment: 3a; no AR-C69931MX; 3b; 500 nmol/L of AR-C69931MX [16].

Gene context of AR-C69931MX

• On the contrary the effect on [Ca2+]i was neither inhibited by AR-C69931MX or by the P2Y1 antagonist MRS-2179 [6].
• METHODS AND RESULTS: By using the selective P2 antagonists MRS2179 and AR-C69931MX, the P2Y12 receptor was found to be involved in thrombin-induced exposure of PS on isolated platelets and consequently in TF-induced thrombin formation in platelet-rich plasma [17].
• AR-C69931MX (10 microM), a specific antagonist of the Gi-coupled P2Y12 ADP receptor, inhibits ERK2 activation induced by thrombin [13].
• The actions of these agonists were significantly inhibited in the presence of the P2Y12 receptor antagonist, AR-C69931MX, but not the P2Y1 receptor antagonist, MRS2179 [18].
• Clopidogrel (300 mg loading dose plus 75 mg daily) significantly inhibited TRAP-induced aggregation, procoagulant activity (annexin V binding) and microparticle production (all P < 0.05) but not as extensively as AR-C69931MX (400 nmol/l) [19].

Analytical, diagnostic and therapeutic context of AR-C69931MX

• Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes [1].
• Placebo or AR-C69931MX (4.0 microg/kg/min for 6 h) pretreatment was administered as an intravenous infusion beginning 15 min before inducing vessel wall injury [10].
• Pharmacological studies at AstraZeneca R&D Charnwood have identified direct, selective, and competitive P2Y (12) antagonists, including cangrelor (also known as AR-C69931MX), which is suitable for intravenous administration, and AZD6140, which is suitable for oral administration [20].
• In the first experiment there were four study groups with unmodified stents: 1a, no AR-C69931MX; 1b, 250 nmol/L; 1c, 750 nmol/L; 1d, 2250 nmol/L of AR-C69931MX [16].
• We assessed the influence of a selective P2Y(12)-receptor antagonist (AR-C69931MX), in conjunction with thrombolytic therapy, on the prevention of platelet aggregation and thrombus formation [11].

References