“Darexaban”的意思、由来-开放百科全书

Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma.^[1] It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation^[2] and possibly ischemic events in acute coronary syndrome.^[3] It is used in form of the maleate. The development of darexaban was discontinued in September 2011.

Factor Xa

Factor Xa (FXa) is an essential blood coagulation factor^[2] that is responsible for the initiation of the coagulation cascade. FXa cleaves prothrombin to its active form thrombin, which then acts to convert soluble fibrinogen to insoluble fibrin and to activate platelets. Stabilization of the platelet aggregation by fibrin mesh ultimately leads to clot formation.^[4]

Metabolism

Darexaban is rapidly absorbed and extensively metabolized in the liver to its active metabolite, darexaban glucuronide (YM-222714) during first pass metabolism via glucuronidation.^[5] The metabolism of darexaban also occurs in the small intestine but to a much lesser extent.^[2] Glucuronidation of darexaban occurs quickly, thus the half life of darexaban itself is short. However, the resultant darexaban glucuronide metabolite has a long half life of approximately 14–18 hours, reaching its maximum levels in the blood 1-1.5 hour post dose.^[2] As a result, darexaban glucuronide is the main determinant of the antithrombotic effects.^[3] Darexaban shows minimal interaction with food and is excreted through the kidneys (urine) and feces.^[6]

Mechanism of action

Darexaban and darexaban glucuronide selectively and competitively inhibit FXa, suppressing prothrombin activity at the sites of blood clot (thrombus) formation. This leads to a decrease in blood clot formation in a dose dependent manner.^[2] Reducing blood clot formation will decrease blood flow blockages, thus possibly lowering the risk of myocardial infarction, unstable angina, venous thrombosis, and ischemic stroke.^[7]

Clinical uses

Atrial fibrillation

Contraindictions

The RUBY-1 phase II trial results show that oral administration of darexaban in combination with the standard dual antiplatelet therapy used for acute coronary syndrome (ACS) patients caused a two- to four-fold increase in bleeding rates and no effect on ACS.^[6] Though there were no cases of fatal bleeding or intracranial haemorrhage, the results of this study questions the concept of adding an oral anticoagulant to standard of care dual antiplatelet therapy in order to prevent recurrent ischemic events after ACS. The development of darexaban was discontinued in September 2011.

References

1. ^Eriksson, B., et al. "A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery." Journal of Thrombosis and Haemostasis (2007): 1660-1665
2. ^¹²³⁴Yoshiyuki, I., et al. "Biochemical and pharmalogical profile of darexaban, an oral direct Xa inhibitor." European Journal of Pharmacology (2011): 49-55
3. ^¹Toshifumi, S., et al. "Identification of UDP-Glucuronosyltransferases Responsible for the Glucuronidation of Darexaban, an Oral Factor Xa Inhibitor, in Human Liver anD Intestine." The American Society for Pharmacology and Experimental Therapeutics (2011): 278-282
4. ^¹Katsung, B., S. Masters and A. Trevor. Basic and Clinical Pharmacology 11th Edition. United States of America: McGraw-Hill, 2009
5. ^Turpie, A., et al. "Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthoplasty. A dose finding study (ONYX-2)." Journal of Thrombosis and Haemostasis (2010): 714-721
6. ^¹{{cite journal | pmid = 21878434 | year = 2011 | last1 = Steg | first1 = PG | last2 = Mehta | first2 = SR | last3 = Jukema | first3 = JW | last4 = Lip | first4 = GY | last5 = Gibson | first5 = CM | last6 = Kovar | first6 = F | last7 = Kala | first7 = P | last8 = Garcia-Hernandez | first8 = A | last9 = Renfurm | first9 = RW | last10 = Granger | first10 = CB | last11 = Ruby-1 | first11 = Investigators | title = RUBY-1: A randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome | volume = 32 | issue = 20 | pages = 2541–54 | doi = 10.1093/eurheartj/ehr334 | pmc = 3295208 | journal = European Heart Journal }}
7. ^Hirayama, F., et al. "Discovery of N-[2-Hydroxy-6-(4-methoxybenamido)phenyl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide (Darexaban, YM150) as a Potent and Orally Available Factor Xa Inhibitor." Journal of Medicinal Chemistry (2011): 8051-8065
8. ^Zhong, Y., et al. "Atrial Fibrillation as a Risk Factor for Stroke: A Retrospective Cohort Study of Hospitalized Medicare Beneficiaries." American Journal of Public Health (1998): 395-400
9. ^Hylek, E., et al. "Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation." The New England Journal of Medicine (2003): 1019-26

词条	Darexaban
释义	Factor Xa Metabolism Mechanism of action Clinical uses Atrial fibrillation Contraindictions References {{Chembox \| ImageFile = Darexaban.svg \| ImageSize = 200px \| IUPACName = N-(3-Hydroxy-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl)-4-methoxybenzamide \| OtherNames = YM150 \|Section1={{Chembox Identifiers \| CASNo = 365462-23-3 \| CASNo_Ref = {{cascite\|correct\|}} \| CASNo1 = 365462-24-4 \| CASNo1_Ref = {{cascite\|correct\|}} \| CASNo1_Comment = (maleate) \| PubChem = 9912771 \| ChemSpiderID = 8088422 \| SMILES = O=C(c1ccc(OC)cc1)Nc2cccc(O)c2NC(=O)c4ccc(N3CCCN(C)CC3)cc4 \| InChI = 1/C27H30N4O4/c1-30-15-4-16-31(18-17-30)21-11-7-19(8-12-21)27(34)29-25-23(5-3-6-24(25)32)28-26(33)20-9-13-22(35-2)14-10-20/h3,5-14,32H,4,15-18H2,1-2H3,(H,28,33)(H,29,34) \| InChIKey = IJNIQYINMSGIPS-UHFFFAOYAJ \| StdInChI = 1S/C27H30N4O4/c1-30-15-4-16-31(18-17-30)21-11-7-19(8-12-21)27(34)29-25-23(5-3-6-24(25)32)28-26(33)20-9-13-22(35-2)14-10-20/h3,5-14,32H,4,15-18H2,1-2H3,(H,28,33)(H,29,34) \| StdInChIKey = IJNIQYINMSGIPS-UHFFFAOYSA-N \|Section2={{Chembox Properties \| C=27 \| H=30 \| N=4 \| O=4 \| Appearance = \| Density = \| MeltingPt = \| BoilingPt = \| Solubility = \|Section3={{Chembox Hazards \| MainHazards = \| FlashPt = \| AutoignitionPt = }} Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma.^[1] It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation^[2] and possibly ischemic events in acute coronary syndrome.^[3] It is used in form of the maleate. The development of darexaban was discontinued in September 2011. Factor Xa Factor Xa (FXa) is an essential blood coagulation factor^[2] that is responsible for the initiation of the coagulation cascade. FXa cleaves prothrombin to its active form thrombin, which then acts to convert soluble fibrinogen to insoluble fibrin and to activate platelets. Stabilization of the platelet aggregation by fibrin mesh ultimately leads to clot formation.^[4] Metabolism Darexaban is rapidly absorbed and extensively metabolized in the liver to its active metabolite, darexaban glucuronide (YM-222714) during first pass metabolism via glucuronidation.^[5] The metabolism of darexaban also occurs in the small intestine but to a much lesser extent.^[2] Glucuronidation of darexaban occurs quickly, thus the half life of darexaban itself is short. However, the resultant darexaban glucuronide metabolite has a long half life of approximately 14–18 hours, reaching its maximum levels in the blood 1-1.5 hour post dose.^[2] As a result, darexaban glucuronide is the main determinant of the antithrombotic effects.^[3] Darexaban shows minimal interaction with food and is excreted through the kidneys (urine) and feces.^[6] Mechanism of action Darexaban and darexaban glucuronide selectively and competitively inhibit FXa, suppressing prothrombin activity at the sites of blood clot (thrombus) formation. This leads to a decrease in blood clot formation in a dose dependent manner.^[2] Reducing blood clot formation will decrease blood flow blockages, thus possibly lowering the risk of myocardial infarction, unstable angina, venous thrombosis, and ischemic stroke.^[7] Clinical uses Atrial fibrillation Atrial fibrillation is an abnormal heart rhythm that causes a reduction in the cardiac output and blood flow to the brain. It also promotes the formation of blood clots in the atrial chambers of the heart.^[4] Atrial fibrillation is associated with an increased risk of embolic stroke due to the increased risk of blood clot development.^[8] Oral anticoagulant drugs such as Darexaban decrease the incidence and severity of stroke in patients with atrial fibrillation by preventing the formation of blood clots.^[9] Contraindictions The RUBY-1 phase II trial results show that oral administration of darexaban in combination with the standard dual antiplatelet therapy used for acute coronary syndrome (ACS) patients caused a two- to four-fold increase in bleeding rates and no effect on ACS.^[6] Though there were no cases of fatal bleeding or intracranial haemorrhage, the results of this study questions the concept of adding an oral anticoagulant to standard of care dual antiplatelet therapy in order to prevent recurrent ischemic events after ACS. The development of darexaban was discontinued in September 2011. References 1. ^Eriksson, B., et al. "A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery." Journal of Thrombosis and Haemostasis (2007): 1660-1665 2. ^¹²³⁴Yoshiyuki, I., et al. "Biochemical and pharmalogical profile of darexaban, an oral direct Xa inhibitor." European Journal of Pharmacology (2011): 49-55 3. ^¹Toshifumi, S., et al. "Identification of UDP-Glucuronosyltransferases Responsible for the Glucuronidation of Darexaban, an Oral Factor Xa Inhibitor, in Human Liver anD Intestine." The American Society for Pharmacology and Experimental Therapeutics (2011): 278-282 4. ^¹Katsung, B., S. Masters and A. Trevor. Basic and Clinical Pharmacology 11th Edition. United States of America: McGraw-Hill, 2009 5. ^Turpie, A., et al. "Prevention of venous thromboembolism with an oral factor Xa inhibitor, YM150, after total hip arthoplasty. A dose finding study (ONYX-2)." Journal of Thrombosis and Haemostasis (2010): 714-721 6. ^¹{{cite journal \| pmid = 21878434 \| year = 2011 \| last1 = Steg \| first1 = PG \| last2 = Mehta \| first2 = SR \| last3 = Jukema \| first3 = JW \| last4 = Lip \| first4 = GY \| last5 = Gibson \| first5 = CM \| last6 = Kovar \| first6 = F \| last7 = Kala \| first7 = P \| last8 = Garcia-Hernandez \| first8 = A \| last9 = Renfurm \| first9 = RW \| last10 = Granger \| first10 = CB \| last11 = Ruby-1 \| first11 = Investigators \| title = RUBY-1: A randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome \| volume = 32 \| issue = 20 \| pages = 2541–54 \| doi = 10.1093/eurheartj/ehr334 \| pmc = 3295208 \| journal = European Heart Journal }} 7. ^Hirayama, F., et al. "Discovery of N-[2-Hydroxy-6-(4-methoxybenamido)phenyl]-4-(4-methyl-1,4-diazepan-1-yl)benzamide (Darexaban, YM150) as a Potent and Orally Available Factor Xa Inhibitor." Journal of Medicinal Chemistry (2011): 8051-8065 8. ^Zhong, Y., et al. "Atrial Fibrillation as a Risk Factor for Stroke: A Retrospective Cohort Study of Hospitalized Medicare Beneficiaries." American Journal of Public Health (1998): 395-400 9. ^Hylek, E., et al. "Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation." The New England Journal of Medicine (2003): 1019-26 {{Antithrombotics}} 5 : Anticoagulants\|Benzamides\|Diazepanes\|Phenols\|Astellas Pharma
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