Fondaparinux

Fondaparinux (trade name Arixtra) is an anticoagulant medication chemically related to low molecular weight heparins. It is marketed by GlaxoSmithKline. A generic version developed by Alchemia is marketed within the US by Dr. Reddy's Laboratories.

Fondaparinux

Clinical data
Trade names	Arixtra
AHFS/Drugs.com	Monograph
License data	EU EMA: by INN US DailyMed: Fondaparinux
Routes of administration	Subcutaneous
ATC code	B01AX05 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only EU: Rx-only
Pharmacokinetic data
Bioavailability	N/A
Protein binding	94%
Metabolism	renally excreted unchanged
Elimination half-life	17-21 hours[1]
Identifiers
CAS Number	104993-28-4 decasodium salt: 114870-03-0
PubChem CID	636380
DrugBank	DB00569
ChemSpider	552174
UNII	J177FOW5JL decasodium salt: X0Q6N9USOZ
ChEMBL	ChEMBL1201202
CompTox Dashboard (EPA)	DTXSID10146903
Chemical and physical data
Formula	C31H43N3Na10O49S8
Molar mass	1728.03 g·mol^−1
3D model (JSmol)	Interactive image
SMILES [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)N[C@@H]5[C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O[C@@H]5O[C@H]1[C@H](O)[C@@H](O)[C@@H](O[C@@H]1C([O-])=O)O[C@@H]4[C@@H](COS([O-])(=O)=O)O[C@H](O[C@H]3[C@H](O)[C@@H](OS([O-])(=O)=O)[C@H](O[C@H]2[C@H](O)[C@@H](NS([O-])(=O)=O)[C@@H](OC)O[C@@H]2COS([O-])(=O)=O)O[C@H]3C([O-])=O)[C@H](NS([O-])(=O)=O)[C@H]4OS([O-])(=O)=O
InChI InChI=1S/C31H53N3O49S8.10Na/c1-69-27-9(33-85(48,49)50)13(37)17(6(74-27)3-71-88(57,58)59)76-31-22(83-91(66,67)68)16(40)21(24(81-31)26(43)44)79-29-10(34-86(51,52)53)19(82-90(63,64)65)18(7(75-29)4-72-89(60,61)62)77-30-15(39)14(38)20(23(80-30)25(41)42)78-28-8(32-84(45,46)47)12(36)11(35)5(73-28)2-70-87(54,55)56;;;;;;;;;;/h5-24,27-40H,2-4H2,1H3,(H,41,42)(H,43,44)(H,45,46,47)(H,48,49,50)(H,51,52,53)(H,54,55,56)(H,57,58,59)(H,60,61,62)(H,63,64,65)(H,66,67,68);;;;;;;;;;/q;10*+1/p-10/t5-,6-,7-,8-,9-,10-,11-,12-,13-,14-,15-,16+,17-,18-,19-,20+,21+,22-,23+,24-,27+,28-,29-,30-,31-;;;;;;;;;;/m1........../s1 Key:XEKSTYNIJLDDAZ-JASSWCPGSA-D
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Medical uses

Clinically, it is used for the prevention of deep vein thrombosis in patients who have had orthopedic surgery as well as for the treatment of deep vein thrombosis and pulmonary embolism.

Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long-term mortality and morbidity.[2]

It has been investigated for use in conjunction with streptokinase.[3]

Comparison to other agents

One potential advantage of fondaparinux over LMWH or unfractionated heparin is that the risk for heparin-induced thrombocytopenia (HIT) is substantially lower. Furthermore, there have been case reports of fondaparinux being used to anti-coagulate patients with established HIT as it has no affinity for PF4. However, its renal excretion precludes its use in patients with renal dysfunction.

Unlike direct factor Xa inhibitors, it mediates its effects indirectly through antithrombin III, but unlike heparin, it is selective for factor Xa.[4]

Pharmacology

Mechanism of action

Fondaparinux is a synthetic pentasaccharide factor Xa inhibitor. Fondaparinux binds antithrombin and accelerates its inhibition of factor Xa.

Apart from the O-methyl group at the reducing end of the molecule, the identity and sequence of the five monomeric sugar units contained in fondaparinux is identical to a sequence of five monomeric sugar units that can be isolated after either chemical or enzymatic cleavage of the polymeric glycosaminoglycans heparin and heparan sulfate (HS). Within heparin and heparan sulfate this monomeric sequence is thought to form the high-affinity binding site for the anti-coagulant factor antithrombin (AT). Binding of heparin or HS to AT has been shown to increase the anti-coagulant activity of antithrombin 1000 fold. In contrast to heparin, fondaparinux does not inhibit thrombin.

Chemistry

Abbreviations

• GlcNS6S = 2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside
• GlcA = β-D-glucopyranuronoside
• GlcNS3,6S = 2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl
• IdoA2S = 2-O-sulfo-α-L-idopyranuronoside
• GlcNS6SOMe = methyl-O-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside

Fondaparinux is only accessible by chemical synthesis. Recently, Supriya Dey et al reported an effective and scalable one-pot synthesis of Fondaparinux[5]. The sequence of monosaccharides is D-GlcNS6S-α-(1,4)-D-GlcA-β-(1,4)-D-GlcNS3,6S-α-(1,4)-L-IdoA2S-α-(1,4)-D-GlcNS6S-OMe, as shown in the following structure:

Fondaparinux

References

1. Walenga, Jeanine M.; Jeske, Walter P.; Fareed, Jawed (2005). "Biochemical and Pharmacologic Rationale for Synthetic Heparin Polysaccharides". Chemistry and Biology of Heparin and Heparan Sulfate. Elsevier. pp. 143–177. doi:10.1016/b978-008044859-6/50006-x. ISBN 978-0-08-044859-6. The elimination half-life of AT-bound fondaparinux is 17–21 h (171,172). The subcutaneous bioavailability of fondaparinux is nearly 100% and it is distributed mainly in the blood (165,173).
2. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators; Yusuf, S.; Mehta, S. R.; Chrolavicius, S.; Afzal, R.; Pogue, J.; Granger, C. B.; Budaj, A.; Peters, R. J.; Bassand, J. P.; Wallentin, L.; Joyner, C.; Fox, K. A. (2006-04-06). "NEJM -- Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes" (PDF). New England Journal of Medicine. 354 (14): 1464–1476. doi:10.1056/NEJMoa055443. hdl:2437/113091. PMID 16537663.
3. Peters RJ, Joyner C, Bassand JP, et al. (February 2008). "The role of fondaparinux as an adjunct to thrombolytic therapy in acute myocardial infarction: a subgroup analysis of the OASIS-6 trial". Eur. Heart J. 29 (3): 324–31. doi:10.1093/eurheartj/ehm616. PMID 18245119.
4. "Medscape.com". Retrieved 2009-01-23.

[5] Dey, S.; Lo, H-. J.; Wong, C. -H “Programmable One-pot Synthesis of Heparin Pentasaccharide Fondaparinux” Org. Lett. 2020, 22, 4638.

External links

• "Fondaparinux". Drug Information Portal. U.S. National Library of Medicine.