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R7 (drug)

Index R7 (drug)

R7 is a small-molecule flavonoid and orally active, potent, and selective agonist of the tropomyosin receptor kinase B (TrkB) – the main signaling receptor for the neurotrophin brain-derived neurotrophic factor (BDNF) – which is under development for the treatment of Alzheimer's disease. It is a structural modification and prodrug of 7,8-dihydroxyflavone (7,8-DHF) with improved potency and pharmacokinetics, namely oral bioavailability and duration. R7 was synthesized by the same researchers who were involved in the discovery of 7,8-DHF. A patent was filed for R7 in 2013 and was published in 2015. In 2016, it was reported to be in the preclinical stage of development. R7 was superseded by R13 because while R7 had a good drug profile in animals, it showed almost no conversion into 7,8-DHF in human liver microsomes. In 2010, 7,8-DHF, a naturally occurring flavonoid, was found to act as an agonist of the TrkB with nanomolar affinity (Kd ≈ 320 nM). Subsequently, 7,8-DHF demonstrated robust efficacy in animal models of Alzheimer's disease and a variety of other conditions, making it a highly promising potential therapeutic agent. Unfortunately, due to the presence of a vulnerable catechol group on its 2-phenyl-4H-chromene ring, 7,8-DHF is extensively conjugated via glucuronidation, sulfation, and methylation during first-pass metabolism in the liver and has a poor oral bioavailability of only 5% in mice upon oral administration. As such, 7,8-DHF itself is a poor candidate for clinical development as an oral medication. R7 is a derivative of 7,8-DHF with carbamate moieties on its hydroxyl groups, thereby protecting it from metabolism. As R7 is a slightly larger molecule than 7,8-DHF, 72.5 mg R7 is molecularly equivalent to 50 mg 7,8-DHF. Relative to a roughly molecularly equivalent dose of 7,8-DHF, the area-under-curve levels of R7 were found to be 7.2-fold higher upon oral administration to mice, and R7 hence has a greatly improved oral bioavailability in mice of approximately 35%. Moreover, whereas 7,8-DHF itself is mostly metabolized in mice within 30 minutes, 7,8-DHF was still detectable in plasma at 8 hours after administration with R7, indicating that R7 sustainably releases 7,8-DHF into circulation. In accordance, the terminal half-life of R7 is about 195 minutes (3.25 hours) in mice. The Tmax of R7 is about 60 minutes in mice, and its Cmax for a 78 mg/kg dose was 262 ng/mL, whereas that for a 50 mg/kg dose of 7,8-DHF was 70 ng/mL. Like 7,8-DHF, administration of R7 has been found to activate the TrkB in vivo in the mouse brain. Moreover, R7 was found to potently activate the TrkB and the downstream Akt signaling pathway upon oral administration, an action that was tightly correlated with plasma concentrations of 7,8-DHF. As such, R7 has shown in vivo efficacy as an agonist of the TrkB, including central activity, similarly to 7,8-DHF. [1]

55 relations: Agonist, Alzheimer's disease, Area under the curve (pharmacokinetics), Benzopyran, Binding selectivity, Bioavailability, Biological half-life, Biotransformation, Blood plasma, Brain, Brain-derived neurotrophic factor, Carbamate, Catechol, Cell signaling, Central nervous system, Chemical synthesis, Circulatory system, Cmax (pharmacology), Derivative (chemistry), Efficacy, First pass effect, Flavonoid, Functional group, Glucuronidation, Hydroxy group, In vivo, Ligand (biochemistry), List of investigational antidepressants, Liver, Metabolism, Methylation, Microsome, Model organism, Moiety (chemistry), Molar concentration, Molecular modification, Mouth, Natural product, Neurotrophin, Oral administration, Patent, Pharmacodynamics, Pharmacokinetics, Phenyl group, Potency (pharmacology), Pre-clinical development, Prodrug, Protein kinase B, R13 (drug), Receptor (biochemistry), ..., Ring (chemistry), Small molecule, Sulfation, Tropomyosin receptor kinase B, 7,8-Dihydroxyflavone. Expand index (5 more) »

Agonist

An agonist is a chemical that binds to a receptor and activates the receptor to produce a biological response.

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Alzheimer's disease

Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a chronic neurodegenerative disease that usually starts slowly and worsens over time.

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Area under the curve (pharmacokinetics)

In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral in a plot of drug concentration in blood plasma vs.

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Benzopyran

Benzopyran is an polycyclic organic compound that results from the fusion of a benzene ring to a heterocyclic pyran ring.

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Binding selectivity

Binding selectivity is defined with respect to the binding of ligands to a substrate forming a complex.

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Bioavailability

In pharmacology, bioavailability (BA or F) is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs.

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Biological half-life

The biological half-life of a biological substance is the time it takes for half to be removed by biological processes when the rate of removal is roughly exponential.

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Biotransformation

Biotransformation is the chemical modification (or modifications) made by an organism on a chemical compound.

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Blood plasma

Blood plasma is a yellowish coloured liquid component of blood that normally holds the blood cells in whole blood in suspension; this makes plasma the extracellular matrix of blood cells.

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Brain

The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.

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Brain-derived neurotrophic factor

Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene.

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Carbamate

A carbamate is an organic compound derived from carbamic acid (NH2COOH).

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Catechol

Catechol, also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula C6H4(OH)2.

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Cell signaling

Cell signaling (cell signalling in British English) is part of any communication process that governs basic activities of cells and coordinates all cell actions.

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Central nervous system

The central nervous system (CNS) is the part of the nervous system consisting of the brain and spinal cord.

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Chemical synthesis

Chemical synthesis is a purposeful execution of chemical reactions to obtain a product, or several products.

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Circulatory system

The circulatory system, also called the cardiovascular system or the vascular system, is an organ system that permits blood to circulate and transport nutrients (such as amino acids and electrolytes), oxygen, carbon dioxide, hormones, and blood cells to and from the cells in the body to provide nourishment and help in fighting diseases, stabilize temperature and pH, and maintain homeostasis.

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Cmax (pharmacology)

Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose.

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Derivative (chemistry)

In chemistry, a derivative is a compound that is derived from a similar compound by a chemical reaction.

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Efficacy

Efficacy is the ability to get a job done satisfactorily.

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First pass effect

The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation.

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Flavonoid

Flavonoids (or bioflavonoids) (from the Latin word flavus meaning yellow, their color in nature) are a class of plant and fungus secondary metabolites.

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Functional group

In organic chemistry, functional groups are specific substituents or moieties within molecules that are responsible for the characteristic chemical reactions of those molecules.

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Glucuronidation

Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids.

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Hydroxy group

A hydroxy or hydroxyl group is the entity with the formula OH.

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In vivo

Studies that are in vivo (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and plants, as opposed to a tissue extract or dead organism.

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Ligand (biochemistry)

In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose.

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List of investigational antidepressants

This is a list of investigational antidepressants, or antidepressants that are currently under development for clinical use in the treatment of mood disorders but are not yet approved.

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Liver

The liver, an organ only found in vertebrates, detoxifies various metabolites, synthesizes proteins, and produces biochemicals necessary for digestion.

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Metabolism

Metabolism (from μεταβολή metabolē, "change") is the set of life-sustaining chemical transformations within the cells of organisms.

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Methylation

In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group.

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Microsome

In cell biology, microsomes are vesicle-like artifacts re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, living cells.

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Model organism

A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms.

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Moiety (chemistry)

In organic chemistry, a moiety is a part of a molecule.

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Molar concentration

Molar concentration (also called molarity, amount concentration or substance concentration) is a measure of the concentration of a chemical species, in particular of a solute in a solution, in terms of amount of substance per unit volume of solution.

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Molecular modification

Molecular modification is chemical alteration of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug.

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Mouth

In animal anatomy, the mouth, also known as the oral cavity, buccal cavity, or in Latin cavum oris, is the opening through which many animals take in food and issue vocal sounds.

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Natural product

A natural product is a chemical compound or substance produced by a living organism—that is, found in nature.

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Neurotrophin

Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

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Oral administration

| name.

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Patent

A patent is a set of exclusive rights granted by a sovereign state or intergovernmental organization to an inventor or assignee for a limited period of time in exchange for detailed public disclosure of an invention.

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Pharmacodynamics

Pharmacodynamics is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs).

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Pharmacokinetics

Pharmacokinetics (from Ancient Greek pharmakon "drug" and kinetikos "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism.

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Phenyl group

In organic chemistry, the phenyl group or phenyl ring is a cyclic group of atoms with the formula C6H5.

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Potency (pharmacology)

In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.

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Pre-clinical development

In drug development, preclinical development, also named preclinical studies and nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) can begin, and during which important feasibility, iterative testing and drug safety data are collected.

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Prodrug

A prodrug is a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug.

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Protein kinase B

Protein kinase B (PKB), also known as Akt, is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration.

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R13 (drug)

R13 is a small-molecule flavonoid and orally active, potent, and selective agonist of the tropomyosin receptor kinase B (TrkB) – the main signaling receptor for the neurotrophin brain-derived neurotrophic factor (BDNF) – which is under development for the potential treatment of Alzheimer's disease.

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Receptor (biochemistry)

In biochemistry and pharmacology, a receptor is a protein molecule that receives chemical signals from outside a cell.

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Ring (chemistry)

In chemistry, a ring is an ambiguous term referring either to a simple cycle of atoms and bonds in a molecule or to a connected set of atoms and bonds in which every atom and bond is a member of a cycle (also called a ring system).

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Small molecule

Within the fields of molecular biology and pharmacology, a small molecule is a low molecular weight (< 900 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm.

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Sulfation

Sulfation or sulfurylation (not to be confused with sulfonation) in biochemistry is the enzyme-catalyzed conjugation of a sulfo group (not a sulfate or sulfuryl group) to another molecule.

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Tropomyosin receptor kinase B

Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene.

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7,8-Dihydroxyflavone

7,8-Dihydroxyflavone (7,8-DHF) is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and primula tree leaves.

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References

[1] https://en.wikipedia.org/wiki/R7_(drug)

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