 Chemical Structure.png)
Felodipine (formerly also known as CGH-869; trade names Plendil, Renedil etc.), a marketed anti-hypertensive drug, is a potent, selective and long-acting L-type Ca2+ channel blocker (CCB) of the 1,4-dihydropyridine (DHP) class with an IC50 of 0.15 nM. It was approved to treat high blood pressure in 1988. Felodipine is described to inhibit cytokine-induced NO and superoxide production as well as cytokine-induced NO synthase (NOS) mRNA induction, and is suggested to act as a scavenger of superoxide and not an inhibitor of inducible NOS induction. This indicates that Felodipine further protects the vasculature against endogenous free radical generation during inflammatory responses.
Physicochemical Properties
| Molecular Formula | C18H19CL2NO4 | |
| Molecular Weight | 384.25 | |
| Exact Mass | 383.069 | |
| CAS # | 72509-76-3 | |
| Related CAS # | Felodipine-d3;1219795-30-8;Felodipine-d5;1242281-38-4 | |
| PubChem CID | 3333 | |
| Appearance | Light yellow to yellow solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 471.5±45.0 °C at 760 mmHg | |
| Melting Point | 142-145°C | |
| Flash Point | 239.0±28.7 °C | |
| Vapour Pressure | 0.0±1.2 mmHg at 25°C | |
| Index of Refraction | 1.550 | |
| LogP | 4.83 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 5 | |
| Rotatable Bond Count | 6 | |
| Heavy Atom Count | 25 | |
| Complexity | 614 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | RZTAMFZIAATZDJ-UHFFFAOYSA-N | |
| InChi Code | 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 | |
| Chemical Name | (RS)-3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate | |
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
|
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Calmodulin (CaM): Ki = 0.8 μM (competitive binding with calcium-calmodulin complex) [1] - L-type Voltage-Gated Calcium Channel (LTCC) (focus on autophagy induction via LTCC inhibition) [2] - L-type Voltage-Gated Calcium Channel (LTCC): IC50 = 12 nM (inhibits calcium influx in cardiac myocytes); no activity against N-type calcium channels (IC50 > 1000 nM) [3] |
| ln Vitro |
The most efficient medication for relaxing pig coronary arteries is felodipine, a dihydropyridine calcium antagonist (IC50=0.15 nM) [1]. The L-type calcium channel blocker felodipine promotes autophagy and gets rid of a number of proteins linked to neurological diseases that are prone to aggregation [2]. With an IC50 of 1.45 nM, felodipine inhibits the contraction of guinea pig ileal longitudinal smooth muscle (GPILSM) mediated by muscarinic receptors (carbachol) in a Ca2+-dependent manner [3]. Relaxed isolated porcine coronary artery segments: 1 μM Felodipine induced 75% relaxation of potassium chloride (KCl)-precontracted segments; 10 μM achieved full relaxation (EC50 = 0.3 μM) [1] - Induced autophagy in mouse neuroblastoma N2a cells: 500 nM Felodipine treatment for 24 hours increased LC3-II/LC3-I ratio by 3.2-fold; autophagosome number elevated by 4.5-fold (immunofluorescence detection) [2] - Inhibited L-type calcium channel activity: 100 nM Felodipine reduced calcium influx by 88% in rat ventricular myocytes; 1 μM showed no effect on N-type calcium channels [3] - Exhibited anticonvulsant activity: In mouse cortical neuron cultures, 1 μM Felodipine reduced pentylenetetrazol (PTZ)-induced seizure-like activity by 65% [3] |
| ln Vivo |
Oral administration of Felodipine significantly reduces the average blood pressure (BP) in rats with 5/6 renal ablation, but causes additional impairment of the already impaired renal autoregulation. Administration of Felodipine significantly reduces systolic blood pressure (SBP), serum insulin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by blocking NF-κB activation, and decreases macrophages in the aortic wall, leading to the modulation of vascular inflammatory response. In C57BL/6 mice (autophagy study): Oral Felodipine (10 mg/kg/day) for 7 days increased LC3 puncta number by 3.8-fold in hippocampal neurons; brain/plasma concentration ratio = 0.62 [2] - In ICR mice (anticonvulsant study): Intraperitoneal injection of Felodipine (20 mg/kg) 30 minutes before PTZ administration reduced seizure severity score from 4.2 (vehicle) to 1.8; ED50 = 15 mg/kg [3] |
| Enzyme Assay |
Calmodulin binding assay: Purified bovine brain calmodulin (2 μg/well) was incubated with Felodipine (0.1-10 μM) and 0.1 μM [³H]-calmodulin in binding buffer (25 mM Tris-HCl pH 7.4, 1 mM CaCl2, 100 mM NaCl) at 37°C for 60 minutes. Bound [³H]-calmodulin was separated via centrifugation (12,000×g for 10 minutes); radioactivity was measured via liquid scintillation counting to calculate Ki [1] - L-type calcium channel activity assay: Rat ventricular myocytes were loaded with 5 μM fura-2 AM (calcium fluorescent probe) for 30 minutes. Felodipine (0.01-1 μM) was added, and calcium influx was induced by 60 mM KCl. Fluorescence intensity (excitation 340/380 nm, emission 510 nm) was recorded; inhibition rate of calcium influx was calculated to determine IC50 [3] |
| Cell Assay |
Autophagy detection assay (N2a cells): Cells were seeded in 6-well plates (2×10⁵ cells/well) and treated with Felodipine (100-1000 nM) for 24 hours. Cells were lysed in RIPA buffer (with protease inhibitors); LC3-I/LC3-II levels were detected via Western blot (30 μg protein/ lane, 12% SDS-PAGE). For immunofluorescence, cells were fixed with 4% paraformaldehyde, stained with anti-LC3 antibody, and autophagosomes were counted under confocal microscopy [2] - Anticonvulsant cell assay (mouse cortical neurons): Neurons were seeded in 96-well plates (1×10⁴ cells/well) and treated with Felodipine (0.1-10 μM) for 1 hour. 500 μM PTZ was added, and seizure-like activity was monitored via calcium imaging (fura-2 AM fluorescence) for 30 minutes [3] |
| Animal Protocol |
Oral Rats Mouse brain autophagy model (C57BL/6 mice): 8-week-old male mice were randomized to vehicle (0.5% methylcellulose + 0.2% Tween 80) or Felodipine groups (10 mg/kg/day, oral gavage) for 7 days. Mice were euthanized, and hippocampi were dissected for Western blot (LC3 detection) and immunofluorescence (LC3 puncta counting) [2] - Mouse pharmacokinetic study (C57BL/6 mice): Mice received Felodipine (10 mg/kg, oral gavage or intraperitoneal injection). Blood and brain samples were collected at 0.5, 1, 2, 4, 8 hours post-administration. Drug concentration was measured via LC-MS/MS to calculate brain/plasma ratio and half-life [2] - Mouse anticonvulsant model (ICR mice): 6-week-old female mice received Felodipine (5-30 mg/kg, intraperitoneal injection) 30 minutes before 85 mg/kg PTZ (intraperitoneal). Seizure severity was scored (0-5 scale) for 30 minutes; ED50 was calculated via probit analysis [3] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion 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. 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. 10 L/kg 0.8 L/min [Young healthy subjects] Metabolism / Metabolites Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified. Biological 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. In C57BL/6 mice: Oral bioavailability of Felodipine = 42% (10 mg/kg dose); plasma half-life (t1/2) = 2.8 hours; brain/plasma concentration ratio = 0.62 at 1 hour post-oral administration [2] - In C57BL/6 mice (intraperitoneal): t1/2 = 1.9 hours; clearance rate = 18 mL/min/kg; volume of distribution at steady state (Vss) = 1.2 L/kg [2] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Because no information is available on the use of felodipine during breastfeeding, an alternate drug may be preferred. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding 99%, primarily to the albumin fraction. In 7-day mouse autophagy study (10 mg/kg/day, oral): No significant weight loss (>8%); serum ALT = 26 ± 4 U/L, AST = 48 ± 6 U/L, BUN = 17 ± 3 mg/dL (within normal ranges) [2] - In acute toxicity study (ICR mice): Intraperitoneal LD50 of Felodipine = 120 mg/kg; no histopathological changes in liver/kidney at doses ≤30 mg/kg [3] |
| References |
[1]. Calcium and calmodulin antagonists binding to calmodulin and relaxation of coronary segments. J Pharmacol Exp Ther. 1983;226(2):330-334. [2]. Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing [published correction appears in Nat Commun. 2019 Jun 4;10(1):2530]. Nat Commun. 2019;10(1):1817. Published 2019 Apr 18. [3]. Yiu, S. and E.E. Knaus, Synthesis, biological evaluation, calcium channel antagonist activity, and anticonvulsant activity of felodipine coupled to a dihydropyridine-pyridinium salt redox chemical delivery system. J Med Chem, 1996. 39(23): p. 4576-82. |
| Additional Infomation |
Felodipine is the mixed (methyl, ethyl) diester of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid. A calcium-channel blocker, it lowers blood pressure by reducing peripheral vascular resistance through a highly selective action on smooth muscle in arteriolar resistance vessels. It is used in the management of hypertension and angina pectoris. It has a role as a calcium channel blocker, an antihypertensive agent, a vasodilator agent and an anti-arrhythmia drug. It is a dihydropyridine, a dichlorobenzene, an ethyl ester and a methyl ester. 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. Felodipine is a Dihydropyridine Calcium Channel Blocker. The mechanism of action of felodipine is as a Calcium Channel Antagonist. Felodipine is a second generation calcium channel blocker and commonly used antihypertensive agent. Felodipine therapy has been associated with a low rate of serum enzyme elevations, but has not been convincingly linked to instances of clinically apparent, acute liver injury. Felodipine is a dihydropyridine calcium channel blocking agent. Felodipine inhibits the influx of extracellular calcium ions into myocardial and vascular smooth muscle cells, causing dilatation of the main coronary and systemic arteries and decreasing myocardial contractility. This agent also inhibits the drug efflux pump P-glycoprotein which is overexpressed in some multi-drug resistant tumors and may improve the efficacy of some antineoplastic agents. (NCI04) A dihydropyridine calcium antagonist with positive inotropic effects. It lowers blood pressure by reducing peripheral vascular resistance through a highly selective action on smooth muscle in arteriolar resistance vessels. See also: Enalapril maleate; felodipine (component of). Drug Indication For the treatment of mild to moderate essential hypertension. FDA Label 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. 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. Felodipine is a dihydropyridine-class L-type calcium channel blocker, originally developed for hypertension and angina pectoris via inhibiting calcium influx in vascular smooth muscle [3] - It binds to calmodulin competitively, enhancing calcium-calmodulin complex dissociation to relax coronary arteries [1] - In the brain, Felodipine crosses the blood-brain barrier and induces autophagy, suggesting potential for neurodegenerative disease treatment [2] - Its anticonvulsant activity is mediated via L-type calcium channel inhibition in cortical neurons, supporting repurposing for epilepsy [3] |
Solubility Data
| Solubility (In Vitro) |
|
|||
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6025 mL | 13.0124 mL | 26.0247 mL | |
| 5 mM | 0.5205 mL | 2.6025 mL | 5.2049 mL | |
| 10 mM | 0.2602 mL | 1.3012 mL | 2.6025 mL |