Regrelor
{{Short description|Chemical compound}}
{{Infobox drug
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| IUPAC_name = [(2S,3aR,4R,6R,6aR)-6-[6-(ethylcarbamoylamino)purin-9-yl]-2-[(E)-2-phenylethenyl]-3a,4,6,6a-tetrahydrofuro[4,3-d][1,3]dioxol-4-yl]methyl dihydrogen phosphate
| image = Regrelor in ChemDraw 16.svg
| image2 = RegrelorSpin.gif
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| CAS_number =787548-03-2
| SMILES = CCNC(=O)NC1=NC=NC2=C1N=CN2C3C4C(C(O3)COP(=O)(O)O)OC(O4)C=CC5=CC=CC=C5
| StdInChI=1S/C22H25N6O8P/c1-2-23-22(29)27-19-16-20(25-11-24-19)28(12-26-16)21-18-17(14(34-21)10-33-37(30,31)32)35-15(36-18)9-8-13-6-4-3-5-7-13/h3-9,11-12,14-15,17-18,21H,2,10H2,1H3,(H2,30,31,32)(H2,23,24,25,27,29)/b9-8+/t14-,15+,17-,18-,21-/m1/s1
| StdInChIKey = NXHAXEBZOXCDKD-XIXRRVGJSA-N
| class = antiplatelet drug
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| PubChem = 11273179
| UNII = Q6C8TY6SW1
| KEGG = D08983
| ChEMBL = 261244
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| ChemSpiderID = 9448187
| C=22 | H=25 | N=6 | O=8 | P=1
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Regrelor (also known as INS50589) is an experimental antiplatelet drug that was under investigation by Merck Sharp and Dohme in human clinical trials. Although it was initially found to be well tolerated in healthy subjects, safety concerns led to cessation of clinical trials.
Medical uses
Regrelor is an experimental drug. It is classified as an antiplatelet medication.{{cite journal | vauthors = Moliterno DJ | title = Advances in antiplatelet therapy for ACS and PCI | journal = Journal of Interventional Cardiology | volume = 21 Suppl 1 | issue = Suppl 1 | pages = S18-24 | date = December 2008 | pmid = 19090933 | doi = 10.1111/j.1540-8183.2008.00409.x | doi-access = free }} It was under investigation for use in blood clotting problems,{{cite web|title=Regrelor | work = Adis Insight |url=http://adisinsight.springer.com/drugs/800022230 |publisher=Springer International Publishing AG|access-date=3 August 2017}} as well as during coronary artery bypass surgery.
=Available forms=
Regrelor is available in an intravenous formulation.
Pharmacology
Regrelor is classified as a purinergic P2 receptor (P2Y12) antagonist.{{cite web|title=Regrelor|url=https://pubchem.ncbi.nlm.nih.gov/compound/Regrelor| work = PubChem | publisher=National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine |access-date=3 August 2017}} Other compounds in the same mechanistic class include clopidogrel and ticagrelor. It is characterized as a reversible, competitive receptor antagonist.{{cite journal | vauthors = Johnson FL, Boyer JL, Leese PT, Crean C, Krishnamoorthy R, Durham T, Fox AW, Kellerman DJ | display-authors = 6 | title = Rapid and reversible modulation of platelet function in man by a novel P2Y(12) ADP-receptor antagonist, INS50589 | journal = Platelets | volume = 18 | issue = 5 | pages = 346–56 | date = August 2007 | pmid = 17654304 | doi = 10.1080/09537100701268741 | s2cid = 31681877 }} The IC50 for antagonism of ADP-induced (P2Y12-mediated) platelet aggregation was 16 nM in vitro.
Regrelor's primary metabolite is called INS51088.
Chemistry
Regrelor is structurally similar to AMP, just like ticagrelor. Regrelor has 4 hydrogen bond donors and 11 acceptors. It is produced as a disodium salt. The two sodium atoms bind the negatively charged phosphate moiety in solution.
=Synthesis=
Regrelor was synthesized from adenosine diphosphate (ADP), an endogenous chemical involved in metabolism.{{cite web | vauthors = Nave CR |title=Adenosine Triphosphate |year=2005 |work=Hyper Physics [serial on the Internet] |publisher=Georgia State University |url=http://hyperphysics.phy-astr.gsu.edu/hbase/biology/atp.html}} The authors noted that the addition of a lipophilic moiety like cinnamaldehyde at the C-2' and C-3' positions, combined with ethylurea at N-6 on the adenine base, yielded regrelor.{{cite journal | vauthors = Douglass JG, Patel RI, Yerxa BR, Shaver SR, Watson PS, Bednarski K, Plourde R, Redick CC, Brubaker K, Jones AC, Boyer JL | display-authors = 6 | title = Lipophilic modifications to dinucleoside polyphosphates and nucleotides that confer antagonist properties at the platelet P2Y12 receptor | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 4 | pages = 1007–25 | date = February 2008 | pmid = 18232657 | doi = 10.1021/jm701348d }}
History
Regrelor was developed around the same time as prasugrel and cangrelor. After Inspire Pharmaceuticals initially developed the drug, it was purchased by Merck Sharp and Dohme.{{cite web|title=Regrelor Disodium|url=http://en.pharmacodia.com/web/drug/1_2212.html| work = Pharmacodia |publisher=Pharmacodia Holding Ltd|access-date=3 August 2017}}
Research
Pre-clinical experiments in rats, dogs, and monkeys found that the drug acted quickly to inhibit platelet aggregation, and that baseline function was restored quickly after discontinuation of treatment.
In a phase 1 clinical trial sponsored by Merck Sharp and Dohme Corporation, regrelor was well tolerated in healthy volunteers.{{ClinicalTrialsGov|NCT00099450|Study of the Tolerability, Pharmacokinetics, and Pharmacodynamics of INS50589 Intravenous Infusion in Healthy Volunteers}} In 2008, phase 2 trials were discontinued. It is believed that further development of the drug was ceased due to safety reasons. In the trial, there was an increased risk of bleeding for patients on regrelor.{{cite book | vauthors = Chackalamannil S, Rotella D, Ward S | title = Comprehensive Medicinal Chemistry | edition = III | publisher = Elsevier | date = 3 June 2017 |page=568 | isbn = 978-0-12-803201-5 }}
References
{{Reflist|30em}}