Clinical data | |
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Routes of administration | Oral |
Pharmacokinetic data | |
Bioavailability | 80-90 % |
Metabolism | 22-38 % |
Elimination half-life | 0.12 – 0.17 h-1 |
Excretion | Renal |
Identifiers | |
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CAS Number | |
PubChem CID | |
ChemSpider | |
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ChEBI | |
CompTox Dashboard (EPA) | |
Chemical and physical data | |
Formula | C15H11NO3 |
Molar mass | 253.25 g·mol−1 |
Melting point | 229–230 °C (444–446 °F) |
Solubility in water | <15 in H2O mg/mL (20 °C) |
Furegrelate, also known as 5-(3-pyridinylmethyl)benzofurancarboxylic acid, is a chemical compound with thromboxane enzyme inhibiting properties that was originally developed by Pharmacia Corporation as a drug to treat arrhythmias, ischaemic heart disorders, and thrombosis [1] but was discontinued. It is commercially available in the form furegrelate sodium salt.
Furegrelate is able to bind to the enzyme thromboxane A2 synthase. By binding to thromboxane A2 synthase it negates the effects and prevents it from acting like a vasoconstrictor. Because of this Furegrelate is capable of preventing several diseases involving thrombosis, the occurrence of blood clots that block veins or arteries. Furegrelate is orally administrable and rapidly absorbed in the blood. Currently no adverse effects of furegrelate are known due to a lack of research, although thromboxane A2 synthase devisentie could be a potential risk.
5-(3-Pyridinylmethyl)benzofurancarboxylic acid, is an achiral, organic molecule containing a pyridine ring and a carboxylic acid group. The compound is a member of the benzofurans and can be found in a variety of forms (free-base, sodium salt and hydrochloric acid salt) all of them variations of the carboxylic acid functionality. [2] Furegrelate in its free-base form is not well-soluble in pH-neutral aqueous environments and can therefore pass the lipophilic cell membranes.
The pyridine functionality of Furegrelate has biologically the most interesting properties. Pyridines are known to have an inhibiting effect on the synthesis of TxA2 Thromboxane - known for platelet aggregation and vasoconstricting properties. Research also showed that pyridines substituted at the -3’ position with aryl or alkyl carboxylic acid groups, undergo a major enhancement of specifically TxA2 synthase inhibition, probably due to a more favourable molecular orientation during the reaction. [2]
Furegrelate is a synthetic compound that cannot be synthesised by the human body. Several pathways were proposed for the synthesis of Furegrelate sodium salt and related compounds by Johnson et al. and is presented in Figure 1. [2] The nitro group of the starting material, 3-(4-nitrobenzyl)pyridine (1), is reduced using hydrogen over palladium on activated carbon to form 3-(4-aminobenzyl)pyridine (2). In the following step, nitric acid was created in situ by mixing sodium nitrite with sulphuric acid in ice-cold water. The nitric acid attaches to the amino group, forming a diazo group. The hydroxyl group is obtained by stirring the diazo intermediate in a hot aqueous sulphuric acid solution, giving product 3. Product 3 was formylated on the ortho-position relative to the hydroxyl group, using an adjusted Duff reaction using hexamine and trifluoroacetic acid (TFA). In the Duff reaction, the formyl carbon is created from hexamine, leading to product 3-(3-hydroxy-4-formylbenzyl)pyridine, 4. Benzofuran-2-carboxylic acid ethyl ester (5), was obtained using a base-promoted reaction with diethyl bromomalonate and sodium hydride on product 4. To increase NaH solubility, a crown ether was used. Ester product 5 was then transformed to Furegrelate sodium salt 6 using methanol and sodium hydroxide in water. Johnson and co-workers synthesised also two other Furegrelate chemical forms: the free-base 7 and hydrochloric acid salt 8 forms.
The starting material, 3-(4-nitrobenzyl)pyridine (1), is commercially available but can also be synthesised from the pyridine-derivative nicotinic acid, as shown in Figure 2. In the first step, nicotinic acid is chlorinated with SOCl3 after which a Friedel-Crafts acylation is performed to form 3-benzoyl pyridine. [3] This compound is reduced using hydrogen gas in combination with a palladium catalyst, creating 3-benzylpyridine. [4] 3-Benzylpyridine can be converted to 3-(4-nitrobenzyl)pyridine using ammonium nitrate and trifluoroacetic anhydride (TFAA) in chloroform. [4] Various intermediate compounds are commercially available, or can be synthesised in multiple ways, but a complete synthetic proposal was made to indicate the synthetic options.
Only one form of furegrelate is commercially available (see 2 structure and reactivity). Its physical form is a crystalline solid. [5] It is sold as a sodium salt. [6]
Furegrelate is an enzyme inhibitor. [5] It combines with the enzyme thromboxane A2 synthase to prevent the normal substrate-enzyme combination and the catalytic reaction. Thromboxane A2, the compound synthesized by this enzyme, promotes the aggregation of platelets and is a vasoconstrictor. The compound plays a role in several diseases involving thrombosis, the occurrence of blood clots that block veins or arteries. [7] Thromboxane is synthesized from a fatty acid called arachidonic acid. In platelets this fatty acid is metabolized to an endoperoxide called prostaglandin H2 by the enzyme cyclooxygenase 1. This endoperoxide is in turn metabolized to thromboxane A2 by thromboxane A2 synthase, a cytochrome P450 enzyme that occurs in the endoplasmic reticulum membrane. [8] Multiple cyclooxygenase inhibitors are already used as drugs against thrombotic diseases. These drugs inhibit both the production of thromboxane and prostacyclin. Furegrelate however, specifically inhibits thromboxane A2 synthase. [7]
The route of administration of furegrelate is oral. The absorption and disposition of the parent drug in male volunteers have been studied after single- and multiple-dose oral administration. The results from the single-dose study indicate that furegrelate is rapidly absorbed in the blood, within maximally 1.0 to 1.7 hr. Distribution, metabolism and elimination happened with a rate constant of 0.12 to 0.17 hr-1. Furegrelate is primarily eliminated by the kidney, with 62 to 78% of the dose excreted as parent drug. [9] Dog experiments indicated that furegrelate is rapidly distributed. The half‐life of the compound was 132 min after an intravenous dose. Oral exposure to the drug had similar absorption and elimination kinetics as the intravenous results. The bioavailability of furegrelate dosed orally was either around 80% based on measurements of the blood concentration or more than 90% based on urinary excretion of the parent compound. [10] Oral absorption of the drug in dogs occurred rapidly. The plasma levels reached a peak in one to two hours after ingestion. The drug was measurable in blood within 30 minutes. Thromboxane A2 is hydrated within about 30 seconds to the biologically inactive thromboxane B2. For this reason thromboxane B2 can be used as an indicator for the inhibition of thromboxane A2 synthase, and thus the presence of furegrelate. [11]
Current studies show no negative side effects of furegrelate due to off target effects in either humans or dogs. Furegrelate does not appear to show any inhibitory effect on thrombin-stimulated PGI2 biosynthesis in human endothelial cells, the 5-lipoxygenase in human neutrophils, or the cyclo-oxygenase in a variety of test systems. [12]
“Studies failed to detect major off-target effects in preclinical testing in dogs or in Phase 1 clinical trials using healthy adult human subjects.” [8]
A possible adverse effect of furegrelate would be thromboxane synthase deficiency due to either too high of a dosage or due to too long administration. Thromboxane synthase deficiency is characterized by mucocutaneous, gastrointestinal, or surgical bleeding. However, this effect has not been studied yet, due to a lack of research in high dosage or long term administration of furegrelate. [13]
The toxicological properties have not been thoroughly investigated. [14]
The effects of furegrelate sodium have been tested using piglets. Three groups of piglets were compared. The first group of piglets were exposed to 21 days of normoxia (N; oxygen tension of 21% FIO2), the second group was exposed to chronic hypoxia (CH; low oxygen tension, 10% FIO2), the third group was exposed to the same chronic hypoxia as group 2, with the addition of 3mg/kg furegrelate 3 times a day. The second group showed a 2.55-fold increase of the pulmonary vascular resistance index (PVRI) compared to the first group. The third group showed a reduction of 34% of the PVRI compared to the second group, and showed an improvement of the right ventricular hypertrophy. When looking at arterial distensibility the second group showed a 33% reduction compared to the first group, the third group showed a reduction of only 20%. Furthermore, the muscularization of small pulmonary arteries was less prominent when comparing group 3 to group 2. Lastly, group 3 showed lower basal and vasodilator-induced transpulmonary pressures compared to group 2. In conclusion the inhibition of the enzyme thromboxane A2 synthase by furegrelate reduces hypoxia induced pulmonary arterial hypertension by preserving the pulmonary vasculature. [8]
Furegrelate reduces renal vasoconstriction of angiotensin II, a blood pressure increasing hormone, in rats. It does this presumably by enhancing the formation of vasodilator prostaglandins. [15] Inhibition of furegrelate induced a proapoptotic disposition of glioma cells in mice. In addition it increased the sensitivity to the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea. This significantly increased the survival time of intracerebral glioma-bearing mice. [16]
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.
Prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are a subclass of eicosanoids and of the prostanoid class of fatty acid derivatives.
Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid. A member of the animal-type heme peroxidase family, it is also known as prostaglandin G/H synthase. The specific reaction catalyzed is the conversion from arachidonic acid to prostaglandin H2 via a short-living prostaglandin G2 intermediate.
Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.
Thromboxane A synthase 1 , also known as TBXAS1, is a cytochrome P450 enzyme that, in humans, is encoded by the TBXAS1 gene.
The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.
Treprostinil, sold under the brand names Remodulin for infusion, Orenitram for oral, and Tyvaso for inhalation, is a vasodilator that is used for the treatment of pulmonary arterial hypertension. Treprostinil is a synthetic analog of prostacyclin (PGI2).
Sodium aurothiomalate is a gold compound that is used for its immunosuppressive anti-rheumatic effects. Along with an orally-administered gold salt, auranofin, it is one of only two gold compounds currently employed in modern medicine.
A prostaglandin antagonist is a hormone antagonist acting upon one or more prostaglandins, a subclass of eicosanoid compounds which function as signaling molecules in numerous types of animal tissues.
Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by activating the thromboxane receptor, which results in platelet-shape change, inside-out activation of integrins, and degranulation. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot. Thromboxane A2 is also a known vasoconstrictor and is especially important during tissue injury and inflammation. It is also regarded as responsible for Prinzmetal's angina.
Aspirin causes several different effects in the body, mainly the reduction of inflammation, analgesia, the prevention of clotting, and the reduction of fever. Much of this is believed to be due to decreased production of prostaglandins and TXA2. Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs, which are reversible inhibitors. However, other effects of aspirin, such as uncoupling oxidative phosphorylation in mitochondria, and the modulation of signaling through NF-κB, are also being investigated. Some of its effects are like those of salicylic acid, which is not an acetylating agent.
Seratrodast (development name, AA-2414; marketed originally as Bronica) is a thromboxane A2 (TXA2) receptor (TP receptor) antagonist used primarily in the treatment of asthma. It was the first TP receptor antagonist that was developed as an anti-asthmatic drug and received marketing approval in Japan in 1997. As of 2017 seratrodast was marketed as Bronica in Japan, and as Changnuo, Mai Xu Jia, Quan Kang Nuo in China.
Cyclooxygenases are enzymes that take part in a complex biosynthetic cascade that results in the conversion of polyunsaturated fatty acids to prostaglandins and thromboxane(s). Their main role is to catalyze the transformation of arachidonic acid into the intermediate prostaglandin H2, which is the precursor of a variety of prostanoids with diverse and potent biological actions. Cyclooxygenases have two main isoforms that are called COX-1 and COX-2. COX-1 is responsible for the synthesis of prostaglandin and thromboxane in many types of cells, including the gastro-intestinal tract and blood platelets. COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells and in the central nervous system. Prostaglandin synthesis in these sites is a key factor in the development of inflammation and hyperalgesia. COX-2 inhibitors have analgesic and anti-inflammatory activity by blocking the transformation of arachidonic acid into prostaglandin H2 selectively.
Ifetroban is a potent and selective thromboxane receptor antagonist. It has been studied in animal models for the treatment of cancer metastasis, myocardial ischemia, hypertension, stroke, thrombosis, cardiomyopathy, and for its effects on platelets. Clinical trials are evaluating the therapeutic safety and efficacy of oral ifetroban capsules for the treatment of cancer metastasis, cardiovascular disease, aspirin exacerbated respiratory disease, systemic sclerosis, and Duchenne muscular dystrophy.
Terbogrel (INN) is an experimental drug that has been studied for its potential to prevent the vasoconstricting and platelet-aggregating action of thromboxanes. Terbogrel is an orally available thromboxane A2 receptor antagonist and a thromboxane A synthase inhibitor. The drug was developed by Boehringer Ingelheim.
Proton pump inhibitors (PPIs) block the gastric hydrogen potassium ATPase (H+/K+ ATPase) and inhibit gastric acid secretion. These drugs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. PPIs also can bind to other types of proton pumps such as those that occur in cancer cells and are finding applications in the reduction of cancer cell acid efflux and reduction of chemotherapy drug resistance.
12-Hydroxyheptadecatrienoic acid (also termed 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, or 12(S)-HHTrE) is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was discovered and structurally defined in 1973 by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg, as a product of arachidonic acid metabolism made by microsomes (i.e. endoplasmic reticulum) isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.
20-Hydroxyeicosatetraenoic acid, also known as 20-HETE or 20-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid, is an eicosanoid metabolite of arachidonic acid that has a wide range of effects on the vascular system including the regulation of vascular tone, blood flow to specific organs, sodium and fluid transport in the kidney, and vascular pathway remodeling. These vascular and kidney effects of 20-HETE have been shown to be responsible for regulating blood pressure and blood flow to specific organs in rodents; genetic and preclinical studies suggest that 20-HETE may similarly regulate blood pressure and contribute to the development of stroke and heart attacks. Additionally the loss of its production appears to be one cause of the human neurological disease, Hereditary spastic paraplegia. Preclinical studies also suggest that the overproduction of 20-HETE may contribute to the progression of certain human cancers, particularly those of the breast.
Lysine acetylsalicylate, also known as aspirin DL-lysine or lysine aspirin, is a more soluble form of acetylsalicylic acid (aspirin). As with aspirin itself, it is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory, antithrombotic and antipyretic properties. It is composed of the ammonium form of the amino acid lysine paired with the conjugate base of aspirin.