Ciraparantag

Ciraparantag
Clinical data
Other names	PER977; N1,N1′-[Piperazine-1,4-diylbis(propane-1,3-diyl)]bis-L-argininamide
Routes of; administration	Intravenous
ATC code	None;
Legal status
Legal status	Investigational;
Pharmacokinetic data
Onset of action	10 min
Duration of action	24 hours
Identifiers
	IUPAC name (2S)-2-Amino-N-[3-[4-[3-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]propyl]piperazin-1-yl]propyl]-5-(diaminomethylideneamino)pentanamide;
CAS Number	1438492-26-2;
PubChem CID	71576543;
ChemSpider	33427375;
UNII	U2R67KV65Q;
KEGG	D10868 ;
Chemical and physical data
Formula	C22H48N12O2
Molar mass	512.708 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CN(CCN1CCCNC(=O)[C@H](CCCNC(=N)N)N)CCCNC(=O)[C@H](CCCNC(=N)N)N;
	InChI InChI=1S/C22H48N12O2/c23-17(5-1-7-31-21(25)26)19(35)29-9-3-11-33-13-15-34(16-14-33)12-4-10-30-20(36)18(24)6-2-8-32-22(27)28/h17-18H,1-16,23-24H2,(H,29,35)(H,30,36)(H4,25,26,31)(H4,27,28,32)/t17-,18-/m0/s1; Key:HRDUUSCYRPOMSO-ROUUACIJSA-N;

Ciraparantag (aripazine) is a drug under investigation as an antidote for a number of anticoagulant (anti-blood clotting) drugs, including factor Xa inhibitors (rivaroxaban, apixaban and edoxaban), dabigatran, and heparins (including fondaparinux, low molecular weight heparins (LMWH), and unfractionated heparin).[1][2]

Medical uses

Ciraparantag significantly reverses anticoagulation induced by a therapeutic dose of edoxaban within 10 minutes following injection.[3] This return to normal haemostasis persists over 24 hours following a single intravenous dose of the drug.[4] In addition to edoxaban, it also reverses the actions of LMWH and dabigatran.[5]

Pharmacology

Mechanism of action

According to in vitro studies, the substance binds directly to anticoagulants via hydrogen bonds and charge-charge interactions [3] from or to various parts of the molecule:[1]

Hydrogen bonds	Rivaroxaban	Apixaban	Edoxaban	Dabigatran	Heparins
Guanidine part	Y		Y	Y	Y
α-Amino group	Y	Y		Y	Y
Amide nitrogen	Y			Y	Y
Amide oxygen		Y	Y

Chemistry

Ciraparantag consists of two L-arginine units connected with a piperazine containing linker chain.[1]

References

Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Herbst 2015 (in German)
Ansell, J. E. (2015). "Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants". Journal of Thrombosis and Thrombolysis. 41 (2): 248–52. doi:10.1007/s11239-015-1288-1. PMID 26449414.
Ansell, Jack E.; Bakhru, Sasha H.; Laulicht, Bryan E.; Steiner, Solomon S.; Grosso, Michael A.; Brown, Karen; Dishy, Victor; Lanz, Hans J.; Mercuri, Michele F.; Noveck, Robert J.; Costin, James C. (February 2017). "Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban". Thrombosis and Haemostasis. 117 (2): 238–245. doi:10.1160/TH16-03-0224. ISSN 0340-6245. PMC 6260118. PMID 27853809.
Laulicht B, Bakhru S, Jiang X et al.Antidote for new oral anticoagulants: Mechanism of action and binding specificity of PER977Internat’l Soc Thromb & Haemost2013. Abstracthttp://www.eventure-online.com/eventure/publicAbstractView.do?id=226718&congressId=6839andhttp://www.perosphere.com/content/presentations/documents/Perosphere_ISTH_Talk
Costin, James C.; Laulicht, Bryan; Bakhru, Sasha; Steiner, Solomon (March 2015). "PER977 reverses low molecular weight heparin in addition to IIa and Xa new oral anticoagulants". Journal of the American College of Cardiology. 65 (10): A2056. doi:10.1016/S0735-1097(15)62056-3.

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[Zsilavecz-1] Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Herbst 2015 (in German)

[2] Ansell, J. E. (2015). "Universal, class-specific and drug-specific reversal agents for the new oral anticoagulants". Journal of Thrombosis and Thrombolysis. 41 (2): 248–52. doi:10.1007/s11239-015-1288-1. PMID 26449414.

[:0-3] Ansell, Jack E.; Bakhru, Sasha H.; Laulicht, Bryan E.; Steiner, Solomon S.; Grosso, Michael A.; Brown, Karen; Dishy, Victor; Lanz, Hans J.; Mercuri, Michele F.; Noveck, Robert J.; Costin, James C. (February 2017). "Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban". Thrombosis and Haemostasis. 117 (2): 238–245. doi:10.1160/TH16-03-0224. ISSN 0340-6245. PMC 6260118. PMID 27853809.

[:1-4] Laulicht B, Bakhru S, Jiang X et al.Antidote for new oral anticoagulants: Mechanism of action and binding specificity of PER977Internat’l Soc Thromb & Haemost2013. Abstracthttp://www.eventure-online.com/eventure/publicAbstractView.do?id=226718&congressId=6839andhttp://www.perosphere.com/content/presentations/documents/Perosphere_ISTH_Talk

[5] Costin, James C.; Laulicht, Bryan; Bakhru, Sasha; Steiner, Solomon (March 2015). "PER977 reverses low molecular weight heparin in addition to IIa and Xa new oral anticoagulants". Journal of the American College of Cardiology. 65 (10): A2056. doi:10.1016/S0735-1097(15)62056-3.