Zotarolimus

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Zotarolimus
Zotarolimus.svg
Clinical data
Other names(42S)-42-Deoxy-42-(1H-tetrazol-1-yl)-rapamycin
ATC code
  • None
Identifiers
  • (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy-3-{(1R)-2-[(1S,3R,4S)-3-methoxy-4-(1H-tetrazol-1-yl)cyclohexyl]-1-methylethyl}-6,8,12,14,20,26-hexamethyl-4,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-heptadecahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontine-1,5,11,28,29(6H,31H)-pentone
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C52H79N5O12
Molar mass 966.21 g·mol−1
3D model (JSmol)
  • CC1CCC2CC(C(=CC=CC=CC(CC(C(=O)C(C(C(=CC(C(=O)CC(OC(=O)C3CCCCN3C(=O)C(=O)C1(O2)O)C(C)CC4CCC(C(C4)OC)n5cnnn5)C)C)O)OC)C)C)C)OC
  • InChI=1S/C52H79N5O12/c1-31-16-12-11-13-17-32(2)43(65-8)28-39-21-19-37(7)52(64,69-39)49(61)50(62)56-23-15-14-18-41(56)51(63)68-44(34(4)26-38-20-22-40(45(27-38)66-9)57-30-53-54-55-57)29-42(58)33(3)25-36(6)47(60)48(67-10)46(59)35(5)24-31/h11-13,16-17,25,30-31,33-35,37-41,43-45,47-48,60,64H,14-15,18-24,26-29H2,1-10H3/b13-11+,16-12+,32-17+,36-25+/t31-,33-,34-,35-,37-,38+,39+,40+,41+,43+,44+,45-,47-,48+,52-/m1/s1
  • Key:CGTADGCBEXYWNE-JUKNQOCSSA-N

Zotarolimus (INN, codenamed ABT-578) is an immunosuppressant. It is a semi-synthetic derivative of sirolimus (rapamycin). It was designed for use in stents with phosphorylcholine as a carrier. Zotarolimus, or ABT-578, was originally used on Abbott's coronary stent platforms to reduce early inflammation and restenosis; however, Zotarolimus failed Abbott's primary endpoint to bring their stent/drug delivery system to market. The drug was sold/distributed to Medtronic for use on their stent platforms, which is the same drug they use today. Coronary stents reduce early complications and improve late clinical outcomes in patients needing interventional cardiology. [1] The first human coronary stent implantation was first performed in 1986 by Puel et al. [1] [2] However, there are complications associated with stent use, development of thrombosis which impedes the efficiency of coronary stents, haemorrhagic and restenosis complications are problems associated with stents. [1]

Contents

These complications have prompted the development of drug-eluting stents. Stents are bound by a membrane consisting of polymers which not only slowly release zotarolimus and its derivatives into the surrounding tissues but also do not invoke an inflammatory response by the body.

Medtronic are using zotarolimus as the anti-proliferative agent in the polymer coating of their Endeavor and Resolute products. [3]

Background

The inherent growth inhibitory properties of many anti-cancer agents make these drugs ideal candidates for the prevention of restenosis. However, these same properties are often associated with cytotoxicity at doses which block cell proliferation. Therefore, the unique cytostatic nature of the immunosuppressant rapamycin was the basis for the development of zotarolimus by Johnson and Johnson. Rapamycin was originally approved for the prevention of renal transplant rejection in 1999. More recently, Abbott Laboratories developed a compound from the same class, zotarolimus (formerly ABT-578), as the first cytostatic agent to be used solely for delivery from drug-eluting stents to prevent restenosis. [4]

Drug-eluting stents

Drug-eluting stents have revolutionized the field of interventional cardiology and have provided a significant innovation for preventing coronary artery restenosis. Polymer coatings that deliver anti-proliferative drugs to the vessel wall are key components of these revolutionary medical devices. The development of stents which elute the potent anti-proliferative agent, zotarolimus, from a synthetic phosphorylcholine-based polymer known for its biocompatible profile. Zotarolimus is the first drug developed specifically for local delivery from stents for the prevention of restenosis and has been tested extensively to support this indication. Clinical experience with the PC polymer is also extensive, since more than 120,000 patients have been implanted to date with stents containing this non-thrombogenic coating. [4]

Structure and properties

Zotarolimus is an analog made by substituting a tetrazole ring in place of the native hydroxyl group at position 42 in rapamycin that is isolated and purified as a natural product from fermentation. This site of modification was found to be the most tolerant position to introduce novel structural changes without impairing biologic activity. The compound is extremely lipophilic, with a very high octanol-water partition coefficient, and therefore has limited water solubility. These properties are highly advantageous for designing a drug-loaded stent containing zotarolimus in order to obtain a slow sustained release of drug from the stent directly into the wall of coronary vessels. The poor water solubility prevents rapid release into the circulation, since elution of drug from the stent will be partly dissolution rate-limited. The slow rate of release and subsequent diffusion of the molecule facilitates the maintenance of therapeutic drug levels eluting from the stent. In addition, its lipophilic character favors crossing cell membranes to inhibit neointimal proliferation of target tissue. The octanol-water partition coefficients of a number of compounds, recently obtained in a comparative study, indicate that zotarolimus is the most lipophilic of all DES drugs [4]

Restenosis

Zotarolimus is used to counteract restenosis. Restenosis is typically described by clinical trials in a binary approach, otherwise known as "binary restenosis" or just "binary stenosis." Binary restenosis is defined as a >50% stenosis in the vessel diameter (diameter stenosis), or >50% loss of the acute luminal gain, also known as "late loss" following the "acute gain" in lumen diameter after stenting. [1] The term "binary" means that patients are placed in 2 groups, those who have >50% stenosis, and those who have <50% stenosis. An occlusion, or the blocking of all blood flow through a vessel, is considered 100% stenosis.

Previously, restenosis was thought to arise due to the development of neointimal thickening as a result of smooth muscle stimulation. [1] However, it is now thought the blood vessel's dilated segment shrinking is the mechanism. [1] This explains why stenting, which increases the luminal area, is so effective in decreasing the occurrence of restenosis. [1] Vessel restenosis is typically detected by angiography, but can also be detected by duplex ultrasound and other imaging techniques.

Restenosis prevention

The major advancement in restenosis prevention is the use of stents. The Stent Restenosis Study (STRESS) indicated that stents lower restenosis incidence to 32% compared to other medical techniques which combine to only lower it to 42%. [1]

Physiological effects

The key biologic event associated with the restenotic process is clearly the proliferation of smooth muscle cells in response to the expansion of a foreign body against the vessel wall. This proliferative response is initiated by the early expression of growth factors such as PDGF isoforms, bFGF, thrombin, which bind to cellular receptors.

However, the key to understanding the mechanism by which compounds like zotarolimus inhibit cell proliferation is based on events which occur downstream of this growth factor binding. The signal transduction events which culminate in cell cycle arrest in the G1 phase are initiated as a result of ligand binding to an immunophilin known as FK binding protein-12. The FK designation was based on early studies conducted with tacrolimus, formerly known as FK-506, which binds this cytoplasmic protein with high affinity.

Subsequent investigations showed that rapamycin also binds to this intracellular target, forming an FKBP12–rapamycin complex which is not in itself inhibitory, but does have the capacity to block an integral protein kinase known as target of rapamycin (TOR). TOR was first discovered in yeast [5] and later identified in eukaryotic cells, where it was designated as mTOR, the mammalian target of rapamycin. The importance of mTOR is based on its ability to phosphorylate a number of key proteins, including those associated with protein synthesis (p70s6kinase) and initiation of translation (4E-BP1).

Of particular significance is the role that mTOR plays in the regulation of p27kip1, an inhibitor of cyclin-dependent kinases such as cdk2. The binding of agents like rapamycin and zotarolimus to mTOR is thought to block mTOR's crucial role in these cellular events, resulting in arrest of the cell cycle, and ultimately, cell proliferation.

Related Research Articles

<span class="mw-page-title-main">Angioplasty</span> Procedure to widen narrow arteries or veins

Angioplasty, is also known as balloon angioplasty and percutaneous transluminal angioplasty (PTA), is a minimally invasive endovascular procedure used to widen narrowed or obstructed arteries or veins, typically to treat arterial atherosclerosis. A deflated balloon attached to a catheter is passed over a guide-wire into the narrowed vessel and then inflated to a fixed size. The balloon forces expansion of the blood vessel and the surrounding muscular wall, allowing an improved blood flow. A stent may be inserted at the time of ballooning to ensure the vessel remains open, and the balloon is then deflated and withdrawn. Angioplasty has come to include all manner of vascular interventions that are typically performed percutaneously.

<span class="mw-page-title-main">Stent</span> Type of medical device

In medicine, a stent is a metal or plastic tube inserted into the lumen of an anatomic vessel or duct to keep the passageway open, and stenting is the placement of a stent. A wide variety of stents are used for different purposes, from expandable coronary, vascular and biliary stents, to simple plastic stents that allow urine to flow between kidney and bladder. "Stent" is also used as a verb to describe the placement of such a device, particularly when a disease such as atherosclerosis has pathologically narrowed a structure such as an artery.

<span class="mw-page-title-main">Sirolimus</span> Pharmaceutical drug

Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumor (PEComa). It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mechanistic target of rapamycin kinase (mTOR) inhibitor that inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2 (IL-2).

<span class="mw-page-title-main">Everolimus</span> Chemical compound

Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours.

<span class="mw-page-title-main">Coronary catheterization</span> Radiography of heart and blood vessels

A coronary catheterization is a minimally invasive procedure to access the coronary circulation and blood filled chambers of the heart using a catheter. It is performed for both diagnostic and interventional (treatment) purposes.

<span class="mw-page-title-main">Restenosis</span> Recurrence of stenosis, a narrowing of a blood vessel

Restenosis is the recurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and subsequently become renarrowed. This is usually restenosis of an artery, or other blood vessel, or possibly a vessel within an organ.

<span class="mw-page-title-main">Percutaneous coronary intervention</span> Medical techniques used to manage coronary occlusion

Percutaneous coronary intervention (PCI) is a non-surgical procedure used to treat narrowing of the coronary arteries of the heart found in coronary artery disease. The process involves combining coronary angioplasty with stenting, which is the insertion of a permanent wire-meshed tube that is either drug eluting (DES) or composed of bare metal (BMS). The stent delivery balloon from the angioplasty catheter is inflated with media to force contact between the struts of the stent and the vessel wall, thus widening the blood vessel diameter. After accessing the blood stream through the femoral or radial artery, the procedure uses coronary catheterization to visualise the blood vessels on X-ray imaging. After this, an interventional cardiologist can perform a coronary angioplasty, using a balloon catheter in which a deflated balloon is advanced into the obstructed artery and inflated to relieve the narrowing; certain devices such as stents can be deployed to keep the blood vessel open. Various other procedures can also be performed.

<span class="mw-page-title-main">Drug-eluting stent</span> Peripheral or coronary stent

A drug-eluting stent (DES) is a peripheral or coronary stent placed into narrowed, diseased peripheral or coronary arteries that slowly release a drug to block cell proliferation. This prevents fibrosis that, together with clots (thrombi), could otherwise block the stented artery, a process called restenosis. The stent is usually placed within the peripheral or coronary artery by an interventional cardiologist or interventional radiologist during an angioplasty procedure.

Phosphorylcholine is the hydrophilic polar head group of some phospholipids, which is composed of a negatively charged phosphate bonded to a small, positively charged choline group. Phosphorylcholine is part of the platelet-activating factor; the phospholipid phosphatidylcholine and sphingomyelin, the only phospholipid of the membrane that is not built with a glycerol backbone. Treatment of cell membranes, like those of RBCs, by certain enzymes, like some phospholipase A2, renders the phosphorylcholine moiety exposed to the external aqueous phase, and thus accessible for recognition by the immune system. Antibodies against phosphorylcholine are naturally occurring autoantibodies that are created by CD5+/B-1 B cells and are referred to as non-pathogenic autoantibodies.

The history of invasive and interventional cardiology is complex, with multiple groups working independently on similar technologies. Invasive and interventional cardiology is currently closely associated with cardiologists, though the development and most of its early research and procedures were performed by diagnostic and interventional radiologists.

Alan W. Heldman is an American interventional cardiologist. Heldman graduated from Harvard College, University of Alabama School of Medicine, and completed residency and fellowship training at Johns Hopkins University School of Medicine. He held positions on the faculty of Johns Hopkins from 1995 to 2007. In 2007, he became clinical chief of cardiology at the University of Miami's Leonard M. Miller School of Medicine.

<span class="mw-page-title-main">Coronary stent</span> Medical apparatus implanted into coronary arteries

A coronary stent is a tube-shaped device placed in the coronary arteries that supply blood to the heart, to keep the arteries open in the treatment of coronary heart disease. It is used in a procedure called percutaneous coronary intervention (PCI). Coronary stents are now used in more than 90% of PCI procedures. Stents reduce angina and have been shown to improve survivability and decrease adverse events in an acute myocardial infarction.

Cypher is a brand of drug-eluting coronary stent from Cordis Corporation, a Cardinal Health company. During a balloon angioplasty, the stent is inserted into the artery to provide a "scaffold" to open the artery. An anti-rejection-type medication, sirolimus, helps to limit the overgrowth of normal cells while the artery heals which reduces the chance of re-blockage in the treated area known as restenosis, and reduces the chances that another procedure is required.

<span class="mw-page-title-main">Bare-metal stent</span> Type of stent without a coating or covering

A bare-metal stent is a stent made of thin, uncoated (bare) metal wire that has been formed into a mesh-like tube. The first stents licensed for use in cardiac arteries were bare metal – often 316L stainless steel. More recent "second generation" bare-metal stents have been made of cobalt chromium alloy. While plastic stents were first used to treat gastrointestinal conditions of the esophagus, gastroduodenum, biliary ducts, and colon, bare-metal stent advancements led to their use for these conditions starting in the 1990s.

<span class="mw-page-title-main">Bioresorbable stent</span>

In medicine, a stent is any device which is inserted into a blood vessel or other internal duct to expand it to prevent or alleviate a blockage. Traditionally, such devices are fabricated from metal mesh and remain in the body permanently or until removed through further surgical intervention. A bioresorbable stent serves the same purpose, but is manufactured from a material that may dissolve or be absorbed in the body.

<span class="mw-page-title-main">Umirolimus</span>

Umirolimus is an immunosuppressant, a macrocyclic lactone, a highly lipophilic derivative of sirolimus. This drug is proprietary to Biosensors International, which uses it in its own drug-eluting stents, and licenses it to partners such as Terumo.

Genous is an endothelial progenitor cell (EPC) capture technology manufactured by OrbusNeich that promotes the accelerated natural healing of the vessel wall after stent implantation. The pro-healing technology has an antibody surface coating that captures circulating CD34+ endothelial progenitor cells to the device, forming a functional endothelial layer over the stent to protect against thrombus and minimize restenosis.

mTOR inhibitors Class of pharmaceutical drugs

mTOR inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

Neointimal hyperplasia refers to proliferation and migration of vascular smooth muscle cells primarily in the tunica intima, resulting in the thickening of arterial walls and decreased arterial lumen space. Neointimal hyperplasia is the major cause of restenosis after percutaneous coronary interventions such as stenting or angioplasty. The term neointima is used because the cells in the hyperplastic regions of the vascular wall have histological characteristics of both intima and normal artery cells.

A dual therapy stent is a coronary artery stent that combines the technology of an antibody-coated stent and a drug-eluting stent. Currently, second-generation drug-eluting stents require long-term use of dual-antiplatelet therapy, which increases the risk of major bleeding occurrences in patients. Compared to drug-eluting stents, dual therapy stents have improved vessel regeneration and cell proliferation capabilities. As a result, dual therapy stents were developed to reduce the long-term need for dual-antiplatelet therapy.

References

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