128270-60-0 Usage
Uses
Used in Alternative Medicine:
Bivalirudin is used as an alternative to ordinary heparin and platelet glycoprotein IIb/IIIa antagonists for patients with unstable angina undergoing percutaneous transluminal coronary angioplasty.
Used in Anticoagulant and Antithrombotic Applications:
Bivalirudin is used as an anticoagulant and antithrombotic agent, selectively inhibiting αand ζ-thrombin, enzymes that exhibit high fibrinogen-clotting activities. It is effective in reducing platelet deposition in a rat carotid endarterectomy model and has been used to prevent ischemic events during angioplasty for thrombus-containing lesions.
Used in Cardiology:
Bivalirudin is used in cardiology as an intravenous treatment for patients with unstable angina undergoing percutaneous transluminal coronary angioplasty. Clinical studies have suggested that the use of bivalirudin is more efficacious and more predictable than unfractionated heparin, with fewer bleeding complications.
Despite some unresolved developmental issues, the attractive properties of Bivalirudin could make it a useful alternative to heparin in a variety of coagulation disorders.
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. "
Originator
Biogen (US)
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.
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.
Harnessing polarity and viscosity to identify green binary solvent mixtures as viable alternatives to DMF in solid-phase peptide synthesis
Albericio, Fernando,Dettner, Frank,Egelund, Peter H. G.,Haselmann, Kim F.,Jadhav, Sandip,Johansson Castro, Henrik,Krüger, Tobias,Lechner, Carolin,Liffert, Raphael,Martin, Vincent,Pedersen, Daniel Sejer,Sch?nleber, Ralph,Thordal Le Quement, Sebastian
, p. 3295 - 3311 (2021)
Solid-phase peptide synthesis (SPPS) enables routine synthesis of virtually any type of peptide sequence and is the preferred method for peptide synthesis in academia and the pharmaceutical industry alike. Still, SPPS typically requires significant amounts of hazardous solvents and thus suffers from a negative environmental footprint. Such drawbacks have spurred numerous initiatives for solvent substitution, reduction and recycling, and a handful solvents have recently been proposed as potential green alternatives toN,N-dimethylformamide (DMF). In this report, we recognise solvent viscosity and polarity in combination as key physicochemical parameters for SPPS and identify green binary solvent mixtures of dimethyl sulfoxide (DMSO) and 1,3-dioxolane or 2-methyl tetrahydrofuran that closely resemble DMF. In a series of reagent dissolution, resin swelling, peptide coupling and Fmoc-removal experiments we show that combining solvents offers unprecedented opportunities to predict and fine-tune the overall solvent properties for different aspects of SPPS. Lastly, the identified green binary solvent mixtures were employed for the synthesis of a range of challenging model peptides and peptide therapeutics on meaningful scale, demonstrating that binary solvent mixtures are viable green alternatives to DMF in SPPS.
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.
SYNTHETIC METHOD OF BIVALIRUNDIN
-
Page/Page column 12; 13, (2020/01/24)
The Active Pharmaceutical Ingredient (API), Bivalirudin, is a 20 amino acid peptide containing one basic and 5 amino acid residues. With a chemical formula of C98H138N24O33 and a molecular weight of 2180.3 g/mol. Bivalirudin is also known as Angiomax. It is a direct thrombin inhibitor indicated for use as an anticoagulant. It provides a method for synthesizing bivalirudin and in particular to the synthetic method of bivalirudin by solid phase peptide synthesis using Fmoc-Leu-Wang resin as a carrier. The method has the advantages of high yield, less by-product and simple separation and purification, and it's time gaining than the prior art, and is suitable for pilot and industrial production.
PEPTIDE SYNTHESIS METHOD
-
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.
IMPROVEMENTS IN SOLID PHASE PEPTIDE SYNTHESIS
-
Paragraph 0071-0076, (2017/08/01)
An improved method of deprotection in solid phase peptide synthesis is disclosed. In particular the deprotecting composition is added in high concentration and small volume to the mixture of the coupling solution, the growing peptide chain, and any excess activated acid from the preceding coupling cycle, and without any draining step between the coupling step of the previous cycle and the addition of the deprotection composition for the successive cycle. Thereafter, the ambient pressure in the vessel is reduced with a vacuum pull to remove the deprotecting composition without any draining step and without otherwise adversely affecting the remaining materials in the vessel or causing problems in subsequent steps in the SPPS cycle.
Solid phase peptide synthesis via side chain attachment
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Page/Page column 19; 26, (2016/08/10)
The present application discloses peptides and peptaibols of high purity may be obtained by solid phase peptide synthesis using as the starting resin hydroxy amino acids, hydroxy amino acid amides, hydroxy amino alcohols or small peptides containing hydroxy amino acids attached to polymers through their side chain.
PROCESS FOR PRODUCTION OF BIVALIRUDIN
-
Paragraph 0129; 0130, (2016/11/24)
The invention relates to methods for the preparation of high purity Bivalirudin. The polypeptide is prepared in a high purity of at least 98.5% (by HPLC), wherein the total impurities amount to less than 1.5%, comprising not more than 0.5% [Asp9-Bivalirudin] and each is impurity less than 1.0%, and preferably having a purity of at least about 99.0% by HPLC, wherein the total impurities amount to less than 1.0%, comprising not more than 0.5% [Asp9-Bivalirudin] and each impurity is less than 0.5%.
Buffer-based method for preparing bivalirudin drug product
-
, (2011/08/06)
A method for preventing the formation of a bivalirudin precipitate during preparation of a pharmaceutical drug product comprising about 250 mg of bivalirudin, a dried bivalirudin drug product, and a concentrated liquid bivalirudin drug product. The method for preventing the formation of a bivalirudin precipitate comprises (i) preparing an aqueous solution comprising a buffer and a pH greater than the isoelectric point of bivalirudin; (ii) adding bivalirudin salt to the aqueous solution to form a bulk solution; (iii) transferring the bulk solution to one or more vessels; and (iv) drying the bulk solution. The buffer may have a pKa of about 4 to less than 7, and a pH greater than the isoelectric point of bivalirudin. The pH of the bulk solution may be maintained at a level greater than the isoelectric point of bivalirudin. Further, the bulk solution may have a final pH of about 4 to about 7.
METHOD FOR PRODUCING BIVALIRUDIN
-
, (2010/12/18)
A method for producing bivalirudin using solid phase peptide synthesis by the following steps: a) mixing a Fmoc-amino acid resin or a Fmoc-peptide resin with a de-protective agent so as to remove Fmoc-; b) in the presence of a condensing agent, condensing a Fmoc- or Boc-amino acid with the amino acid or the peptide bound to the resin; c) repeating the steps a) and b) to yield a peptide resin represented by Formula I, (SEQ?ID?NO.?1) Boc-D-Phe1-Pro2-Arg(Pbf)3-Pro4-Gly5-Gly6-Gly7- Gly8-Asn(Trt)9-Gly10-Asp(OtBu)11-Phe12-Glu (OtBu)13-Glu(OtBu)14-Ile15-Pro16-Glu(OtBu)17-Glu (OtBu)18-Tyr(tBu)19-Leu20-Resin?(I) and d) in the presence of a cleavage agent, separating the peptide from the resin to yield bivalirudin represented by Formula II (SEQ ID NO. 2). D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe- Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu?(II) Based on its total volume, the de-protective agent is composed of between 3 and 20% of piperidine and between 0.5 and 10% of bicyclic amidine. The method is low in cost and the resultant bivalirudin has high purity.
