Cangrelor

Cangrelor
Names
IUPAC name
[dichloro-[[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl)purin-9-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]methyl]phosphonic acid
Identifiers
ATC code B01AC25
163706-06-7 Yes
ChEMBL ChEMBL1097279 
ChemSpider 8029718 
IUPHAR ligand 1776
Jmol-3D images Image
PubChem 9854012
UNII 6AQ1Y404U7 Yes
Properties
Molecular formula
 C17H25Cl2F3N5O12P3S2
Molar mass 776.36 g·mol−1
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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Infobox references

Cangrelor is a P2Y12 inhibitor under investigation as an antiplatelet drug[1] for intravenous application. Some P2Y12 inhibitors are used clinically as effective inhibitors of adenosine diphosphate-mediated platelet activation and aggregation.[1] Unlike clopidogrel (Plavix), which is a prodrug, cangrelor is an active drug not requiring metabolic conversion.

Poor interim results led to the abandonment of the two CHAMPION clinical trials in mid-2009.[2] The BRIDGE study, for short term use prior to surgery, continues.[3] The CHAMPION PHOENIX trial was a randomized study of over 11,000 patients published in 2013. It found usefulness of cangrelor in patients getting cardiac stents. Compared with clopidogrel given around the time of stenting, intravenous ADP-receptor blockade with cangrelor significantly reduced the rate of stent thrombosis and myocardial infarction.[4] Reviewers have questioned the methodology of the trial.[5]

Medical use

According to recent phase 3 randomized trials, a cangrelor–clopidogrel combination is safe and has been found to be more effective than standard clopidogrel treatment at reducing ischemic events in the heart, without increasing major bleeding in the treatment of stenotic coronary arteries.[6] The advantages of this drug combination are most prominent in patients with myocardial infarction.[6]

Available antiplatelet drugs have delayed onset and offset of action.[6] Since cangrelor’s effects are immediate and quickly reversed, it is a more desirable drug for elective treatment of stenotic coronary arteries, high risk acute coronary syndromes treated with immediate coronary stenting, and for bridging those surgery patients who require P2Y12 inhibition.[6]

Current evidence regarding cangrelor therapy is limited by the lack studies assessing cangrelor administration in conjunction with either prasugrel or ticagrelor.[6]

Pharmacology

Cangrelor is a high-affinity, reversible inhibitor of P2Y12 receptors that causes almost complete inhibition of ADP-induced platelet aggregate.[7] It is a modified ATP derivative stable to enzymatic degradation.[7] It does not require metabolic conversion to an active metabolite . This allows cangrelor’s immediate effect after infusion,[7] and the therapeutic effects can be maintained with continuous infusion.[8] The pharmacokinetics of cangrelor has allow it to rapidly achieve steady-state concentrations with a clearance of 50 L/h and a half-life of 2.6 to 3.3 minutes. Cessation of its administration is associated with rapid removal, and normal platelet function is restored within 1 hour.[8][7]

Adverse effects

Despite fewer bleeding events during cardiac surgery, cangrelor carries the risk of potential autoimmune reactions manifesting as dyspnea.[9] Potential mechanisms for dyspnea following cangrelor treatment include: repeated binding and unbinding cycles, impaired platelet turnover, and lung sequestration or apoptosis of overloaded destructive platelets.[9] The dyspnea risks following cangrelor treatment, suggest a common mechanism linking transfusion-related acute lung injury, dyspnea, and reversible platelet inhibition.[9]

The risk of dyspnea after intravenous cangrelor is smaller when compared with other reversible platelet P2Y12 receptor inhibitors, however, it is still significantly higher when compared to irreversible oral antiplatelet drugs or intravenous glycoprotein IIb/IIIa inhibitors; which do not increase the incidence of dyspnea at all.[9]

References

  1. ↑ 1.0 1.1 Cangrelor Attenuates Coated-Platelet Formation
  2. ↑ CHAMPION Trials With Cangrelor Stopped for Lack of Efficacy
  3. ↑ What Cangrelor Failure Means to Medicines
  4. ↑ Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events (2013) Bhatt, DL etal. New England Journal of Medicine March 10, 2013 doi:10.1056/NEJMoa1300815 (published initially online).
  5. ↑ Lange, RA and Hillis, LD (March 10, 2013). "The Duel between Dual Antiplatelet Therapies". New England Journal of Medicine. doi:10.1056/NEJMe1302504.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Kubica, J. et al. (2014). "Cangrelor: An Emerging Therapeutic Option for Patients with Coronary Artery Disease". Curr Med Res Opin 30 (5): 813–28. doi:10.1185/03007995.2014.880050. PMID 24393016.
  7. ↑ 7.0 7.1 7.2 7.3 Angiolillo, Dominick J., and Piera Capranzano (2008). "Pharmacology of Emerging Novel Platelet Inhibitors". American Heart Journal 156 (2): 10S–5S.
  8. ↑ 8.0 8.1 Bhatt et al. (2013). "Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events". New England Journal of Medicine 368: 1303–1313. doi:10.1056/nejmoa1300815.
  9. ↑ 9.0 9.1 9.2 9.3 Serebruany V.L. et al. (2014). "Dyspnea and Reversibility of Antiplatelet Agents: Ticagrelor, Elinogrel, Cangrelor, and Beyond". Cardiology 127: 20–24. doi:10.1159/000354876.