Cangrelor
{{Short description|Chemical compound}}
{{Use dmy dates|date=June 2023}}
{{Drugbox
| image = Cangrelor structure.svg
| width = 300
| tradename = Kengreal, Kengrexal
| Drugs.com = {{drugs.com|monograph|cangrelor-tetrasodium}}
| MedlinePlus =
| DailyMedID = Cangrelor
| pregnancy_AU =
| pregnancy_category =
| routes_of_administration = Intravenous
| class =
| ATC_prefix = B01
| ATC_suffix = AC25
| ATC_supplemental =
| legal_AU =
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| legal_BR =
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| legal_CA = Rx-only
| legal_CA_comment = {{cite web | title=Details for: Kengrexal | website=Health Canada | date=30 November 2023 | url=https://dhpp.hpfb-dgpsa.ca/dhpp/resource/102353 | access-date=3 March 2024}}{{cite web | title=Notice: Multiple Additions to the Prescription Drug List (PDL) [2023-03-08] | website=Health Canada | date=8 March 2023 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/mutliple-additions-2023-03-08.html | access-date=21 March 2023}}{{cite web | title=Summary Basis of Decision for Kengrexal | website=Health Canada | date=23 May 2023 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/SBD1684935203980 | access-date=5 June 2023}}
| legal_DE =
| legal_DE_comment =
| legal_NZ =
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| legal_UK =
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| legal_US = Rx-only
| legal_EU = Rx-only
| legal_EU_comment =
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| bioavailability = 100% (IV)
| protein_bound = ~97–98%.
| metabolism = Rapid deactivation in the circulation (independent of CYP system)
| elimination_half-life = ~3–6 minutes
| excretion = Kidney (58%), Bile duct (35%)
| index2_label = as salt
| IUPHAR_ligand = 1776
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 163706-06-7
| PubChem = 9854012
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB06441
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6AQ1Y404U7
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D03359
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D03361
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1097279
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 90841
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 8029718
| IUPAC_name = [dichloro-
| C=17 | H=25 | Cl=2 | F=3 | N=5 | O=12 | P=3 | S=2
| smiles = CSCCNC1=NC(=NC2=C1N=CN2[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(O)OP(=O)(C(P(=O)(O)O)(Cl)Cl)O)O)O)SCCC(F)(F)F
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C17H25Cl2F3N5O12P3S2/c1-43-5-3-23-12-9-13(26-15(25-12)44-4-2-16(20,21)22)27(7-24-9)14-11(29)10(28)8(38-14)6-37-42(35,36)39-41(33,34)17(18,19)40(30,31)32/h7-8,10-11,14,28-29H,2-6H2,1H3,(H,33,34)(H,35,36)(H,23,25,26)(H2,30,31,32)/t8-,10-,11-,14-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = PAEBIVWUMLRPSK-IDTAVKCVSA-N
| synonyms = AR-C69931MX
}}
Cangrelor, sold under the brand name Kengreal among others, is a P2Y12 inhibitor FDA approved as of June 2015 as an antiplatelet drug{{cite journal | vauthors = Norgard NB, Hann CL, Dale GL | title = Cangrelor attenuates coated-platelet formation | journal = Clinical and Applied Thrombosis/Hemostasis | volume = 15 | issue = 2 | pages = 177–182 | date = 2009 | pmid = 18796456 | doi = 10.1177/1076029608321437 | s2cid = 23639481 }} for intravenous application. Some P2Y12 inhibitors are used clinically as effective inhibitors of adenosine diphosphate-mediated platelet activation and aggregation. 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.[http://www.medscape.com/viewarticle/702828 CHAMPION Trials With Cangrelor Stopped for Lack of Efficacy] The BRIDGE study, for short term use prior to surgery, continues.{{cite web | vauthors = Napodano J | date = 13 May 2009 | url = http://seekingalpha.com/article/137521-what-cangrelor-failure-means-to-medicines | title = What Cangrelor Failure Means to Medicines | work = Seeking Alpha }} 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.{{cite journal | vauthors = Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimský P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Généreux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA | display-authors = 6 | title = Effect of platelet inhibition with cangrelor during PCI on ischemic events | journal = The New England Journal of Medicine | volume = 368 | issue = 14 | pages = 1303–1313 | date = April 2013 | pmid = 23473369 | doi = 10.1056/NEJMoa1300815 | doi-access = free }} Reviewers have questioned the methodology of the trial.{{cite journal | vauthors = Lange RA, Hillis LD | title = The duel between dual antiplatelet therapies | journal = The New England Journal of Medicine | volume = 368 | issue = 14 | pages = 1356–1357 | date = April 2013 | pmid = 23473370 | doi = 10.1056/NEJMe1302504 }}
Medical use
According to phase III 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. The advantages of this drug combination are most prominent in patients with myocardial infarction.{{cite journal | vauthors = Kubica J, Kozinski M, Navarese EP, Tantry U, Kubica A, Siller-Matula JM, Jeong YH, Fabiszak T, Andruszkiewicz A, Gurbel PA | display-authors = 6 | title = Cangrelor: an emerging therapeutic option for patients with coronary artery disease | journal = Current Medical Research and Opinion | volume = 30 | issue = 5 | pages = 813–828 | date = May 2014 | pmid = 24393016 | doi = 10.1185/03007995.2014.880050 | s2cid = 30451326 }}
Available antiplatelet drugs have delayed onset and offset of action. 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.
Evidence regarding cangrelor therapy is limited by the lack studies assessing cangrelor administration in conjunction with either prasugrel or ticagrelor.
Cangrelor been approved for adults undergoing percutaneous coronary intervention (PCI).{{cite press release | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm452172.htm | archive-url = https://web.archive.org/web/20150623214645/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm452172.htm | archive-date = 23 June 2015 | title = FDA approves new antiplatelet drug used during heart procedure |publisher = U.S. Food and Drug Administration | date = 22 June 2015 | url-status = dead }}
Pharmacology
Cangrelor is a high-affinity, reversible inhibitor of P2Y12 receptors that causes almost complete inhibition of ADP-induced platelet aggregate.{{cite journal | vauthors = Angiolillo DJ, Capranzano P | title = Pharmacology of emerging novel platelet inhibitors | journal = American Heart Journal | volume = 156 | issue = 2 Suppl | pages = S10–S15 | date = August 2008 | pmid = 18657681 | doi = 10.1016/j.ahj.2008.06.004 | authorlink1 = Dominick Angiolillo }} It is a modified ATP derivative stable to enzymatic degradation. It does not require metabolic conversion to an active metabolite. This allows cangrelor's immediate effect after infusion, and the therapeutic effects can be maintained with continuous infusion.{{cite journal | vauthors = Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimský P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Généreux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA | display-authors = 6 | title = Effect of platelet inhibition with cangrelor during PCI on ischemic events | journal = The New England Journal of Medicine | volume = 368 | issue = 14 | pages = 1303–1313 | date = April 2013 | pmid = 23473369 | doi = 10.1056/nejmoa1300815 | doi-access = free }} The pharmacokinetics of cangrelor has allowed 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.
Adverse effects
Despite fewer bleeding events during cardiac surgery, cangrelor carries the risk of potential autoimmune reactions manifesting as breathlessness.{{cite journal | vauthors = Serebruany VL, Sibbing D, DiNicolantonio JJ | title = Dyspnea and reversibility of antiplatelet agents: ticagrelor, elinogrel, cangrelor, and beyond | journal = Cardiology | volume = 127 | issue = 1 | pages = 20–24 | year = 2014 | pmid = 24192670 | doi = 10.1159/000354876 | s2cid = 207707382 }} 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. The dyspnea risks following cangrelor treatment, suggest a common mechanism linking transfusion-related acute lung injury, dyspnea, and reversible platelet inhibition.
The risk of breathlessness 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 breathlessness at all.
Chemistry
= Synthesis =
Cangrelor is synthesized starting from 2-thiobarbituric acid and peracetyl-D-ribofuranose.{{cite journal | vauthors = Flick AC, Ding HX, Leverett CA, Kyne RE, Liu KK, Fink SJ, O'Donnell CJ | title = Synthetic Approaches to the New Drugs Approved During 2015 | journal = Journal of Medicinal Chemistry | volume = 60 | issue = 15 | pages = 6480–6515 | date = August 2017 | pmid = 28421763 | doi = 10.1021/acs.jmedchem.7b00010 | doi-access = free }}{{Cite patent|number=CN105481922A|title=一种坎格雷洛中间体的制备方法|gdate=2016-04-13|invent1=周峰|invent2=金华|invent3=郑永勇|invent4=黄美花|url=https://patents.google.com/patent/CN105481922A/en?oq=CN105481922A}}
The synthesis starts with the selective S-alkylation of 2-thiobarbituric acid, followed by nitration with nitric acid, leading to the nitrated dihydroxypyrimidine. Treatment with phosphorus oxychloride affords the corresponding dichloropyrimidine. Subsequently, the nitro group is reduced using iron as the reductant, yielding the aniline derivative. This is cyclized to the purine using triethyl orthoformate and hydrochloric acid.
N,O-bis-(trimethylsilyl)acetamide is used to protect the anilinic nitrogen, allowing for the selective N9-alkylation of the compound with peracetyl-D-ribofuranose using trimethylsilyl triflate.{{Cite journal | vauthors = Almond MR, Collins JL, Reitter BE, Rideout JL, Freeman GA, St Clair MH |date=1991-10-07 |title=Synthesis of 2-amino-9-(3′-azido-2′,3′-dideoxy-beta-D-erythro-pentofuranosyl)-6-methoxy-9H-purine (AzddMAP) and AzddGuo |url=https://www.sciencedirect.com/science/article/pii/S0040403900935457 |journal=Tetrahedron Letters |language=en |volume=32 |issue=41 |pages=5745–5748 |doi=10.1016/S0040-4039(00)93545-7 |issn=0040-4039|url-access=subscription }}
The 5'-OH is converted to a phosphodichloridate using phosphorus oxychloride in triethyl phosphate as the solvent.{{cite journal | vauthors = Yoshikawa M, Kato T, Takenishi T | title = A novel method for phosphorylation of nucleosides to 5'-nucleotides | journal = Tetrahedron Letters | volume = 8 | issue = 50 | pages = 5065–5068 | date = December 1967 | pmid = 6081184 | doi = 10.1016/S0040-4039(01)89915-9 }} This is converted to Cangrelor without isolation by reaction with dichloromethylenebis(phosphonic acid) and tributylamine as the base.
References
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{{Antithrombotics}}
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Category:Adenosine diphosphate receptor inhibitors