| Identification | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Name | Felodipine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Accession Number | DB01023 (APRD00374) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Type | small molecule | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Groups | approved | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | Felodipine is a long-acting 1,4-dihydropyridine calcium channel blocker (CCB)b. It acts primarily on vascular smooth muscle cells by stabilizing voltage-gated L-type calcium channels in their inactive conformation. By inhibiting the influx of calcium in smooth muscle cells, felodipine prevents calcium-dependent myocyte contraction and vasoconstriction. Felodipine is the most potent CCB in use and is unique in that it exhibits fluorescent activity. In addition to binding to L-type calcium channels, felodipine binds to a number of calcium-binding proteins, exhibits competitive antagonism of the mineralcorticoid receptor, inhibits the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase, and blocks calcium influx through voltage-gated T-type calcium channels. Felodipine is used to treat mild to moderate essential hypertension. |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Structure |
Download: MOL | SDF | SMILES | InChI Display: 2D Structure | 3D Structure |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Synonyms |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Brand names |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Brand name mixtures |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Categories |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CAS number | 72509-76-3 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Weight |
Average: 384.254 Monoisotopic: 383.069113515 |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Chemical Formula | C18H19Cl2NO4 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| InChI Key | InChIKey=RZTAMFZIAATZDJ-UHFFFAOYSA-N | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| InChI |
InChI=1S/C18H19Cl2NO4/c1-5-25-18(23)14-10(3)21-9(2)13(17(22)24-4)15(14)11-7-6-8-12(19)16(11)20/h6-8,15,21H,5H2,1-4H3
Plain Text
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| IUPAC Name |
3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SMILES |
CCOC(=O)C1=C(C)NC(C)=C(C1C1=C(Cl)C(Cl)=CC=C1)C(=O)OC
Plain Text
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mass Spec | Not Available | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Taxonomy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Kingdom | Organic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Classes |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Substructures |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pharmacology | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Indication | For the treatment of mild to moderate essential hypertension. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pharmacodynamics | Felodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. It was widely accepted that CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction; however, some studies have shown that felodipine also binds to and inhibits T-type calcium channels. T-type calcium channels are most commonly found on neurons, cells with pacemaker activity and on osteocytes. The pharmacologic significance of T-type calcium channel blockade is unknown. Felodipine also binds to calmodulin and inhibits calmodulin-dependent calcium release from the sarcoplasmic reticulum. The effect of this interaction appears to be minor. Another study demonstrated that felodipine attenuates the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) by binding to the PDE-1B1 and PDE-1A2 enzyme subunits. CaMPDE is one of the key enzymes involved in cyclic nucleotides and calcium second messenger systems. Felodipine also acts as an antagonist to the mineralcorticoid receptor by competing with aldosterone for binding and blocking aldosterone-induced coactivator recruitment of the mineralcorticoid receptor. Felodipine is able to bind to skeletal and cardiac muscle isoforms of troponin C, one of the key regulatory proteins in muscle contraction. Though felodipine exhibits binding to many endogenous molecules, its vasodilatory effects are still thought to be brought about primarily through inhibition of voltage-gated L-type calcium channels. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mechanism of action | Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through voltage-gated L-type calcium channels. It reversibly competes against nitrendipine and other DHP CCBs for DHP binding sites in vascular smooth muscle and cultured rabbit atrial cells. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Absorption | Is completely absorbed from the gastrointestinal tract; however, extensive first-pass metabolism through the portal circulation results in a low systemic availability of 15%. Bioavailability is unaffected by food. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Volume of distribution |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Protein binding | 99%, primarily to the albumin fraction. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Metabolism |
Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Route of elimination | Although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Half life | 17.5-31.5 hours in hypertensive patients; 19.1-35.9 hours in elderly hypertensive patients; 8.5-19.7 in healthy volunteers. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clearance |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Toxicity | Symptoms of overdose include excessive peripheral vasodilation with marked hypotension and possibly bradycardia. Oral rat LD50 is 1050 mg/kg. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Affected organisms |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pathways |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pharmacoeconomics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Manufacturers |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Packagers |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dosage forms |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prices |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patents | Not Available | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Properties | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| State | solid | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Melting point | 145oC | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Experimental Properties |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Predicted Properties |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| References | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Synthesis Reference | Not Available | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| General Reference |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| External Links |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ATC Codes |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| AHFS Codes |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| PDB Entries | Not Available | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| FDA label | show (227.5 KB) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MSDS | show (55.4 KB) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Interactions | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Drug Interactions | Not Available | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Food Interactions |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Targets |
|---|
|
1. Voltage-dependent L-type calcium channel subunit alpha-1C Pharmacological action: yesActions: inhibitor Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds Organism class: humanUniProt ID: Q13936 ![]() Gene: CACNA1C ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
2. Voltage-dependent calcium channel subunit alpha-2/delta-1 Pharmacological action: yesActions: inhibitor Calcium channel protein which plays an important role in excitation-contraction coupling Organism class: humanUniProt ID: P54289 ![]() Gene: CACNA2D1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
3. Voltage-dependent L-type calcium channel subunit beta-2 Pharmacological action: yesActions: inhibitor The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting Organism class: humanUniProt ID: Q08289 ![]() Gene: CACNB2 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
4. Voltage-dependent L-type calcium channel subunit alpha-1D Pharmacological action: yesActions: inhibitor Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1D gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA) Organism class: humanUniProt ID: Q01668 ![]() Gene: CACNA1D ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
5. Voltage-dependent L-type calcium channel subunit alpha-1S Pharmacological action: yesActions: inhibitor Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1S gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the "high-voltage activated" (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin- GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle Organism class: humanUniProt ID: Q13698 ![]() Gene: CACNA1S ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
6. Voltage-dependent T-type calcium channel subunit alpha-1H Pharmacological action: unknownActions: inhibitor Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1H gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by nickel and mibefradil. A particularity of this type of channels is an opening at quite negative potentials, and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes Organism class: humanUniProt ID: O95180 ![]() Gene: CACNA1H ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
7. Voltage-dependent calcium channel subunit alpha-2/delta-2 Pharmacological action: unknownActions: inhibitor Organism class: human UniProt ID: Q9NY47 ![]() Gene: CACNA2D2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
8. Calmodulin Pharmacological action: unknownActions: other Calmodulin mediates the control of a large number of enzymes and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number of protein kinases and phosphatases Organism class: humanUniProt ID: P62158 ![]() Gene: CALM1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
9. Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B Pharmacological action: unknownActions: inhibitor Has a preference for cGMP as a substrate Organism class: humanUniProt ID: Q01064 ![]() Gene: PDE1B Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
10. Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A Pharmacological action: unknownActions: inhibitor Has a higher affinity for cGMP than for cAMP Organism class: humanUniProt ID: P54750 ![]() Gene: PDE1A ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
11. Mineralocorticoid receptor Pharmacological action: unknownActions: antagonist Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels Organism class: humanUniProt ID: P08235 ![]() Gene: NR3C2 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
12. Troponin C, skeletal muscle Pharmacological action: unknownActions: other Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components:Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments Organism class: humanUniProt ID: P02585 ![]() Gene: TNNC2 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
13. Troponin C, slow skeletal and cardiac muscles Pharmacological action: unknownActions: other Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components:Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments Organism class: humanUniProt ID: P63316 ![]() Gene: TNNC1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
|
| Enzymes |
|---|
|
Actions: substrate, inhibitor
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide UniProt ID: P08684![]() Gene: CYP3A4 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: substrate
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics UniProt ID: P20815![]() Gene: CYP3A5 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: substrate
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics UniProt ID: P24462![]() Gene: CYP3A7 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: inhibitor
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol) UniProt ID: P10632![]() Gene: CYP2C8 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: inhibitor
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan UniProt ID: P11712![]() Gene: CYP2C9 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: inhibitor
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants UniProt ID: P10635![]() Gene: CYP2D6 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
|
| Transporters |
|---|
|
1. Multidrug resistance protein 1 Actions: inhibitorEnergy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells UniProt ID: P08183![]() Gene: ABCB1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
|
| Comments |
|---|
This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.