128270-60-0 Usage
Anticoagulants
Bivalirudin is a kind of synthetic novel anticoagulants. It is the direct, specific and reversible inhibitor of thrombin. It was developed by the Swiss Basset (Biogen) originally. Then it was transferred to the United States Medicines Company, and approved for marketing in the United States in 2000. Its anticoagulant ingredient is a kind of 20 peptides derived from hirudin. Bivalirudin can specifically bind with catalytic site and the anion binding site of whether thrombin that is in the blood circulation or thrombus-bound thrombin, thus directly inhibiting thrombin activity. And its role is characterized by short, reversible. Early clinical studies show that the anticoagulation treatment of bivalirudin is good. And the incidence of bleeding events is low. So its use is safer than traditional heparin therapy. It is mainly used for the prevention of angioplasty interventional treatment of ischemic complications of unstable angina pectoris before and after.
Bivalirudin has a inhibitory effect on soluble and thrombus-bound thrombin in vitro. That effect cannot be affected by products that are released by platelet, and it can extend plasma activated partial thromboplastin time, thrombin time and prothrombin time of normal human with a dose-dependent manner. It is suitable for percutaneous coronary intervention (PCI) unstable angina. In 2010, domestic PCI operation cases reached 300,000. The annual compound growth rate was over 30%. This showed that sales prospects of bivalirudin after the listing are considerable.
Clinically experiments prove that bivalirudin is more effective than the current mainstream unfractionated heparin/low molecular weight heparin and platelet glycoprotein receptor antagonist in applications around PCI. Especially the risk of bleeding has a significant reduction, and the use safety of anticoagulants is greatly improved:
1. It can significantly reduce the incidence of bleeding in elective PCI patients. The total clinical outcome risk fell 14%.
2. It does not cause antibody-mediated thrombocytopenia.
3. Reversibly bind with thrombin. Short half-life. Hard to develop ischemic and hemorrhagic complications.
4. It is not mainly excreted through the kidneys and can be safely used in patients with renal impairment.
The above information is edited by the lookchem of Duan Yalan.
Dosage
The first dose 0.75 mg/kg is injected intravenously. Then it is continuously injected intravenously with 1.75 mg/kg per hour by percutaneous coronary intervention. ACT should be monitored after first intravenous injection for 5 minutes. If necessary, 0.3mg/kg bivalirudin is injected again. After percutaneous coronary intervention treatment, it is continued to use for 4h. If necessary, 0.2 mg/kg bivalirudin per hour is continuously injected for 20h. When it is used, using 5mL water for injection to dissolve, and then using 50 mL normal saline to be diluted to 5mg/mL solution.
Adverse reactions and precautions
1. To guard against the occurrence of bleeding, including intracranial hemorrhage, thrombocytopenia. Intravenously injection should stop immediately when a sudden drop in blood pressure and blood volume.
2. Back pain, headaches, insomnia, anxiety, abdominal pain, diarrhea, nausea, vomiting, low blood pressure can be seen. When serious bivalirudin should be discontinued. Patients with renal dysfunction should reduce its dosage.
3. Patients allergic to bivalirudin and active bleeding should be banned. Women, infants, breast-feeding women should be careful to use this product.
4. Bivalirudin cannot bind with plasma proteins and red blood cells. When bivalirudin is used with heparin, warfarin, or thrombolytic drugs, it will increase the possibility of bleeding of patients. Once the excessive use, it should be discontinued. The product can be cleared by hemodialysis.
Clinical evaluation
In order to prove the efficacy and safety of bivalirudin in the treatment of patients with acute coronary syndrome (ACS), the researchers designed the ACUITY clinical research.
ACUITY clinical trial was to compare the efficacy and safety of bivalirudin with traditional heparin platelet glycoprotein Ⅱb/Ⅲa inhibitor therapy in high-risk ACS patients. ACUITY results published in a recent issue of the "New England Journal of Medicine" showed that the efficacy of bivalirudin alone is same with traditional anticoagulant drugs. While preventing ischemic events, it can significantly reduce bleeding.
ACUITY trial chooses 13,819 patients from 17 countries with high-risk non-ST segment elevation acute coronary syndrome. Patients were randomly divided into three group: unfractionated heparin or low molecular weight heparin and glycoprotein Ⅱb/Ⅲa inhibitor combination group, bivalirudin and glycoprotein Ⅱb/Ⅲa inhibitor combination group and bivalirudin alone group. The primary endpoint is ischemic composite endpoint occurred in 30 days (death, myocardial infarction or unplanned revascularization due to ischemia), major bleeding events and overall clinical outcomes (the sum of ischemic or serious bleeding events). The results showed that compared with heparin and glycoprotein Ⅱb/Ⅲa inhibitor combination group, the incidence of ischemic events in bivalirudin alone group did not significantly increase (7.8% vs 7.3%;. P = 0.32 ). Bleeding risk decreased 47% (3.0% vs. 5.7%; P <0.001), and the overall clinical outcomes were also improved significantly (10.1% vs.11.7%; P = 0.015). Using bivalirudin alone is not inferior to the combination of heparin and glycoprotein Ⅲb/Ⅲa inhibito. In addition, the combinations of bivalirudin and glycoprotein Ⅱb/Ⅲa inhibitor are also not inferior to heparin and glycoprotein Ⅱb/Ⅲa inhibitors, but no advantage at all.
Stone, the study leader in Columbia University Medical Center Stone, believes that " for high-risk ACS patients with early intervention therapy, bivalirudin is a suitable alternative to heparin or enoxaparin when used with glycoprotein Ⅱb/Ⅲa inhibitors. Compared with the combinations of heparin and glycoprotein Ⅱb/Ⅲa inhibitors or the combinations of bivalirudin and glycoprotein Ⅱb/Ⅲa inhibitor, bivalirudin treatment can make patients to have a more significant net clinical benefit. And event-free survival in 30 days can be improved. "
Uses
Different sources of media describe the Uses of 128270-60-0 differently. You can refer to the following data:
1. Alternative medicine as ordinary heparin and platelet glycoprotein IIb/IIIa antagonists.
2. Anticoagulant; antithrombotic.
Description
Different sources of media describe the Description of 128270-60-0 differently. You can refer to the following data:
1. Bivalirudin is an inhibitor of α- and ζ-thrombin (Kis = 2.56 and 1.84 nM, respectively), enzymes that exhibit high fibrinogen-clotting activities. It is selective for α- and ζ-thrombin, lacking activity at trypsin and γ-thrombin, which lacks clotting activity, at a >1,000-fold excess of bivalirudin. Bivalirudin inhibits α-thrombin-stimulated activation of the clotting factors Factor X, Factor V, and prothrombin in contact-activated plasma at a concentration of 0.1 μM. Administration of bivalirudin (0.5-1.5 mg/kg, i.v.) reduces platelet deposition in a rat carotid endarterectomy model in a dose-dependent manner. Formulations containing bivalirudin have been used to prevent ischemic events during angioplasty for thrombus-containing lesions.
2. Bivalirudin was launched in New Zealand as an anticoagulant for i.v. treatment of
patients with unstable angina undergoing percutaneous transluminal coronary angioplasty.
Bivalirubin is a synthetic 20 amino acid peptide rationally modeled on hirudin (residues 53-
64), the most potent and specific naturally-occuring known inhibitor of thrombin, the
enzyme that plays a key role in hemostasis and blood clot formation. This peptide is a
direct thrombin inhibitor that maintains the unique bivalent binding properties of hirudin to
the catalytic site and to the fibrin-recognition exosite of the enzyme, so acting directly on
thrombin with high affinity and specificity. In vitro studies demonstrated that alpha- and
zeta-thrombins, both with the higher fibrinogen-procoagulant activities, were inhibited. In
rats receiving high doses of bivalirudin, the platelet deposition in carotide was reduced by
63% compared to controls. The results of clinical studies, conducted only in patients
receiving concomitant aspirin, suggested that the use of bivalirudin was more efficacious
and more predictable than unfractionated heparin, with fewer bleeding complications.
Despite some unresolved developmental issues, the attractive properties of this novel
agent could make it a useful alternative to heparin in a variety of coagulation disorders.
Originator
Biogen (US)
Definition
ChEBI: A synthetic peptide of 20 amino acids, comprising D-Phe, Pro, Arg, Pro, Gly, Gly, Gly, Gly, Asn, Gly, Asp, Phe, Glu, Glu, Ile, Pro, Glu, Glu, Tyr, and Leu in sequence. A congener of hirudin (a naturally occurring drug found in the saliva o
the medicinal leech), it a specific and reversible inhibitor of thrombin, and is used as an anticoagulant.
Manufacturing Process
A 20 amino acid polypeptide [1], bivalirudin (hirulog) is a synthetic version of
hirudin. Its amino-terminal D-Phe-Pro-Arg-Pro domain, which interacts with
the active site of thrombin, is linked via four Gly residues to a dodecapeptide
analogue of the carboxy-terminal of hirudin. Like hirudin, bivalirudin also
forms a 1:1 stoichiometric complex with thrombin. Once bound, however, the
Arg-Pro bond at the amino-terminal of bivalirudin is cleaved by thrombin,
thereby restoring active site functions of the enzyme complexes of α-thrombin
[2].
Hirulog-8 has the formula: H-(D-Phe)-Pro-Arg-Pro-(Gly)4-Asn-Gly-Asp-Phe-
Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH. Hirulog-8 was synthesized by
conventional solid-phase peptide synthesis employing an Applied Biosystems
430 A Peptide Synthesizer. This peptide was synthesized using BOC-L-Leucine-
O-divinylbenzene resin. Additional t-BOC-amino acids (Peninsula Laboratories, Belmont, Calif.) used included BOC-O-2,6-dichlorobenzyl tyrosine, BOC-Lglutamic
acid (γ-benzyl ester), BOC-L-proline, BOC-L-isoleucine, BOC-Lphenylalanine,
BOC-L-aspartic acid (β-benzyl ester), BOC-glycine, BOC-Lasparagine,
BOC-L-phenylalanine, and BOC-L-arginine. In order to achieve
higher yields in synthesis, the (Gly)4 linker segment was attached in two
cycles of manual addition of BOC-glycylglycine (Beckman Biosciences, Inc.,
Philadelphia, Pa.). After completion of synthesis, the peptide was fully
deprotected and uncoupled from the divinylbenzene resin by treatment with
anhydrous HF:p-cresol:ethylmethyl sulfate (10:1:1, v/v/v). Following removal
from the resin, the peptide was lyophilized to dryness.
Crude Hirulog-8 was purified by reverse-phase HPLC employing an Applied
Biosystems 151A liquid chromatographic system and a Vydac C18 column
(2.2x25 cm). The column was equilibrated in 0.1% TFA/water and developed
with a linear gradient of increasing acetonitrile concentration from 0 to 80%
over 45 minutes in the 0.1% TFA at a flow-rate of 4.0 ml/min. The effluent
stream was monitored for absorbance at 229 nm and fractions were collected
manually. We purified 25-30 mg of crude Hirulog-8 by HPLC and recovered
15-20 mg of pure peptide.
The structure of purified Hirulog-8 was confirmed by amino acid and sequence
analyses.
Brand name
Angiomax (Medicinova).
Therapeutic Function
Anticoagulant
Biochem/physiol Actions
Bivalirudin is a specific and reversible bivalent direct thrombin inhibitor. Bivalirudin specifically binds to both the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin.
Mechanism of action
Bivalirudin is a rapid-onset, short-acting DTI that binds to both the active site and the exosite-1 of
thrombin. Unlike lepirudin, bivalirudin is a reversible inhibitor of both free thrombin and thrombin
bound to fibrin. This reversibility is possible because the bound bivalirudin undergoes cleavage at
the second N-terminal proline to release the portion of the drug bound to the active site. The
carboxyl-terminal portion of bivalirudin dissociates from thrombin to regenerate thrombin. Bivalirudin does not bind to plasma protein.
Pharmacokinetics
Bivalirudin is administered via intravenous bolus injection, followed by continuous infusion (Table
31.4). The drug exhibits a rapid onset and a short duration of action. Bivalirudin is eliminated by
renal excretion. It has been suggested that dosage adjustments be made in patients with severe
renal impairment and in patients undergoing dialysis. Approximately 30% is eliminated unchanged
along with proteolytic cleavage products. Because of the reversible nature of bivalirudin the drug
exhibits less risk of bleeding than other antithrombotics, and there have been no reported cases of
antibody formation to bivalirudin.
Clinical Use
Bivalirudin, a 20-amino-acid peptide, has been approved for use in patients with unstable angina
undergoing percutaneous coronary intervention.
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: increased risk of haemorrhage with IV
diclofenac and ketorolac.
Antiplatelets and anticoagulants: increased risk of
bleeding.
Thrombolytics: may increase risk of bleeding
complications; enhance effect of bivalirudin.
Metabolism
As a peptide, bivalirudin is expected to undergo catabolism
to its constituent amino acids, with subsequent recycling of
the amino acid in the body pool. Bivalirudin is metabolised
by proteases, including thrombin. The primary metabolite
resulting from the cleavage of Arg3
-Pro4
bond of the
N-terminal sequence by thrombin is not active because of
the loss of affinity to the catalytic active site of thrombin.
references
[1]. shammas n w. bivalirudin: pharmacology and clinical applications[j]. cardiovascular drug reviews, 2005, 23(4): 345-360.
Check Digit Verification of cas no
The CAS Registry Mumber 128270-60-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,8,2,7 and 0 respectively; the second part has 2 digits, 6 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 128270-60:
(8*1)+(7*2)+(6*8)+(5*2)+(4*7)+(3*0)+(2*6)+(1*0)=120
120 % 10 = 0
So 128270-60-0 is a valid CAS Registry Number.
InChI:InChI=1/C98H138N24O33/c1-5-52(4)82(96(153)122-39-15-23-70(122)92(149)114-60(30-34-79(134)135)85(142)111-59(29-33-78(132)133)86(143)116-64(43-55-24-26-56(123)27-25-55)89(146)118-67(97(154)155)40-51(2)3)119-87(144)61(31-35-80(136)137)112-84(141)58(28-32-77(130)131)113-88(145)63(42-54-18-10-7-11-19-54)117-90(147)66(45-81(138)139)110-76(129)50-107-83(140)65(44-71(100)124)109-75(128)49-106-73(126)47-104-72(125)46-105-74(127)48-108-91(148)68-21-13-38-121(68)95(152)62(20-12-36-103-98(101)102)115-93(150)69-22-14-37-120(69)94(151)57(99)41-53-16-8-6-9-17-53/h6-11,16-19,24-27,51-52,57-70,82,123H,5,12-15,20-23,28-50,99H2,1-4H3,(H2,100,124)(H,104,125)(H,105,127)(H,106,126)(H,107,140)(H,108,148)(H,109,128)(H,110,129)(H,111,142)(H,112,141)(H,113,145)(H,114,149)(H,115,150)(H,116,143)(H,117,147)(H,118,146)(H,119,144)(H,130,131)(H,132,133)(H,134,135)(H,136,137)(H,138,139)(H,154,155)(H4,101,102,103)/t52-,57+,58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,82-/m0/s1
128270-60-0Relevant articles and documents
AJIPHASE: A Highly Efficient Synthetic Method for One-Pot Peptide Elongation in the Solution Phase by an Fmoc Strategy
Takahashi, Daisuke,Inomata, Tatsuji,Fukui, Tatsuya
, p. 7803 - 7807 (2017)
We previously reported an efficient peptide synthesis method, AJIPHASE, that comprises repeated reactions and isolations by precipitation. This method utilizes an anchor molecule with long-chain alkyl groups as a protecting group for the C-terminus. To further improve this method, we developed a one-pot synthesis of a peptide sequence wherein the synthetic intermediates were isolated by solvent extraction instead of precipitation. A branched-chain anchor molecule was used in the new process, significantly enhancing the solubility of long peptides and the operational efficiency compared with the previous method, which employed precipitation for isolation and a straight-chain aliphatic group. Another prerequisite for this solvent-extraction-based strategy was the use of thiomalic acid and DBU for Fmoc deprotection, which facilitates the removal of byproducts, such as the fulvene adduct.
Protein Modification at Tyrosine with Iminoxyl Radicals
Ishiyama, Takashi,Kanai, Motomu,Maruyama, Katsuya,Oisaki, Kounosuke,Sakai, Kentaro,Seki, Yohei,Togo, Takaya
supporting information, p. 19844 - 19855 (2021/11/30)
Post-translational modifications (PTMs) of proteins are a biological mechanism for reversibly controlling protein function. Synthetic protein modifications (SPMs) at specific canonical amino acids can mimic PTMs. However, reversible SPMs at hydrophobic amino acid residues in proteins are especially limited. Here, we report a tyrosine (Tyr)-selective SPM utilizing persistent iminoxyl radicals, which are readily generated from sterically hindered oximes via single-electron oxidation. The reactivity of iminoxyl radicals with Tyr was dependent on the steric and electronic demands of oximes; isopropyl methyl piperidinium oxime 1f formed stable adducts, whereas the reaction of tert-butyl methyl piperidinium oxime 1o was reversible. The difference in reversibility between 1f and 1o, differentiated only by one methyl group, is due to the stability of iminoxyl radicals, which is partly dictated by the bond dissociation energy of oxime O-H groups. The Tyr-selective modifications with 1f and 1o proceeded under physiologically relevant, mild conditions. Specifically, the stable Tyr-modification with 1f introduced functional small molecules, including an azobenzene photoswitch, to proteins. Moreover, masking critical Tyr residues by SPM with 1o, and subsequent deconjugation triggered by the treatment with a thiol, enabled on-demand control of protein functions. We applied this reversible Tyr modification with 1o to alter an enzymatic activity and the binding affinity of a monoclonal antibody with an antigen upon modification/deconjugation. The on-demand ON/OFF switch of protein functions through Tyr-selective and reversible covalent-bond formation will provide unique opportunities in biological research and therapeutics.
PEPTIDE SYNTHESIS METHOD
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Paragraph 0379-0380, (2018/08/20)
The present invention has an object of providing a peptide synthesis method using a carrier capable of reversibly repeating the dissolved state and the insolubilized state, wherein the problem of an amino acid active species existing in the reaction system in de-protection reaction can be easily solved. The present invention provides a peptide synthesis method comprising the following steps: a step of condensing an N-Fmoc protected amino acid with a peptide having a C-terminal protected with a carrier which is crystallized according to a change of a composition of a dissolving solvent, in the presence of a condensing agent, to obtain an N-Fmoc-C-carrier protected peptide, a step of adding an alkylamine having 1 to 14 carbon atoms or hydroxyl amine to the reaction system, a step of de-protecting the N-terminal, and a step of changing the composition of the solvent dissolving the C-carrier protected peptide, to crystallize and separate the peptide.
