3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

• ChemBase编号: 896
• 分子式: C18H19Cl2NO4
• 平均质量: 384.25376
• 单一同位素质量: 383.06911345
• SMILES: Clc1c(C2C(=C(NC(=C2C(=O)OC)C)C)C(=O)OCC)cccc1Cl
• Canonical SMILES: CCOC(=O)C1=C(C)NC(=C(C1c1cccc(c1Cl)Cl)C(=O)OC)C
• 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
• InChIKey: RZTAMFZIAATZDJ-UHFFFAOYSA-N

名称和登记号

名称

• IUPAC标准名: 3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
• IUPAC传统名: felodipine
• 商标名: AGON SR; Agon; Feloday; Felodur ER; Felogard; Flodil; Hydac; Lexxel; Modip; Munobal; Munobal Retard; Penedil; Perfudal; Plandil; Plendil; Plendil Depottab; Plendil ER; Plendil Retard; Preslow; Prevex; Renedil; Splendil
• 别名: 4-(2,3-Dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic Acid Ethyl Methyl Ester; Flodil; 3-ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; 4-(2,3-Dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylic acid ethyl methyl ester; Felodipine; Plendil; Renedil; Feloday; Felodipina [INN-Spanish]; Felodipine [Usan:Ban:Inn]; Felodipinum [INN-Latin]; Dl-Felodipine; felodipine; Felodipine

登记号

• CAS号: 72509-76-3
• MDL号: MFCD00868316
• PubChem SID: 46506968; 160964359; 24278449
• PubChem CID: 3333

理论计算性质

JChem

• 质子受体: 3
• 质子供体: 1
• LogD (pH = 5.5): 3.1918502
• LogD (pH = 7.4): 3.436203
• Log P: 3.4404075
• 摩尔折射率: 99.1982 cm^3
• 极化性: 37.720104 Å^3
• 极化表面积: 64.63 Å^2
• 可自由旋转的化学键: 6
• 里宾斯基五规则: true

ALOGPS 2.1

• Log P: 4.36
• LOG S: -4.73
• 溶解度: 7.15e-03 g/l

分子性质

理化性质

• 溶解度: 19.7 mg/L; Acetone; Chloroform; DMSO: soluble28 mg/mL; H2O: insoluble; Methanol
• 外观: light yellow solid; Off-White to Pale Yellow Solid
• 熔点: 144-146°C
• 疏水性(logP): 3.8; 5.297

安全信息

• 保存条件: -20°C; -20°C Freezer
• RTECS编号: US7968700
• 欧盟危险性物质标志: 有害性(Harmful) (Xn)
• 德国WGK号: 3
• 危险公开号: 22
• GHS危险品标识: GHS07
• GHS警示词: Warning
• GHS危险声明: H302
• 个人保护装置: dust mask type N95 (US), Eyeshields, Gloves

药理学性质

• 相关基因信息: human ... CACNA2D1(781)

产品相关信息

• 纯度: 95%
• 成盐信息: Free Base
• Empirical Formula (Hill Notation): C18H19NO4Cl2

详细说明

DrugBank - DB01023

• Drug Groups: approved; investigational
• 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.
• Indication: For the treatment of mild to moderate essential hypertension.
• Pharmacology: 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.
• Toxicity: Symptoms of overdose include excessive peripheral vasodilation with marked hypotension and possibly bradycardia. Oral rat LD₅₀ is 1050 mg/kg.
• Affected Organisms: Humans and other mammals
• Biotransformation: Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified.
• 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.
• 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.
• Protein Binding: 99%, primarily to the albumin fraction.
• 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.
• Distribution: * 10 L/kg
• Clearance: * 0.8 L/min [Young healthy subjects]
• References: Dunselman PH, Edgar B: Felodipine clinical pharmacokinetics. Clin Pharmacokinet. 1991 Dec;21(6):418-30. [Pubmed]
• External Links: Wikipedia; RxList; PDRhealth; Drugs.com

Selleck Chemicals - S1885

Research Area

• Description: Cardiovascular Disease

Biological Activity

• Description: Felodipine (Plendil) is a selective L-type Ca^2+ channel blocker with IC50 of 0.15 nM.
• Targets: L-type Ca^2+ channel
• IC50: 0.15 nM ^[1]
• In Vitro: Felodipine significantly relaxes KCl-contracted porcine coronary segments by blocking the Ca^2+ channels, displaying ~50 times more potent than nifedipine (IC50 of ~8 nM) and ~430 times than verapamil (IC50 of ~65 nM). ^[1] Felodipine significantly induces the transcription and secretion of IL-6 and IL-8 with ED50 values of 5.8 nM and 5.3 nM in primary human VSMC and lung fibroblasts, respectively, while propranolol or furosemide fails to affect the expression of the two IL genes. ^[2] Felodipine blocks the muscarinic receptor-mediated (carbachol) Ca^2+-dependent contraction of guinea pig ileum longitudinal smooth muscle (GPILSM) with an IC50 of 1.45 nM. ^[3] Felodipine at low concentration of 0.1 μM is sufficient to increases NOx generation, Ca^2+-dependent NOS activity, and eNOS protein mass in rat endothelial cells. ^[4] Felodipine (10 μM) reduces nuclear translocation of p42/44 mitogen-activated protein kinase and Elk-1 activation stimulated by PDGF-BB, leading to the inhibition of human SMC proliferation. ^[5] Felodipine modestly blocks the Ca_v3.2 T-type Ca^2+-channel with an IC50 of 6.8 μM. ^[6]
• In 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. ^[7] 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. ^[8]
• Clinical Trials: A Phase I study to evaluate the pharmacokinetic interaction between Candesartan and Felodipine in a combination package compared to the separate intake of the reference brands Atacand and Splendil after a fasting period has been completed.
• Features: Unlike many other Ca^2+ channel blockers, Felodipine does not exhibit cardiac side effects due to its significant selectivity toward vascular smooth muscle relative to myocardial tissue.

Protocol

• Protocol: Kinase Assay ^[1]
• The effect of Felodipine on tension in coronary segments: The cylindrical coronary segments from porcine hearts are inverted and fixed horizontally between a stationary bottom pin and a top pin connected to the lever of a force-displacement transducer precalibrated with standard weights on a Grass model 5D polygraph. The cylindrical segments are bathed in 25 mL of PSS in a water jacketed tissue bath at 37 °C. The bath solution is bubbled continuously with a mixture of 95% O₂-5% CO₂. An initial resting tension of 10 g is set during a 2-hour equilibration period. After the equilibration, three to four successive contraction-relaxation cycles are induced with 35 mM KCl and subsequent washes with PSS until reproducible contractions are obtained. After the final response reached and maintained steady tension (16-25 g above resting tension), a cumulative dose-response curve for Felodipine is obtained. Additional aliquots of Felodipine are added only after the response to the previous dose has plateaued. The concentration of Felodipine that half-maximally relaxes the coronary from KCl-induced contraction (IC50) is determined from dose response curve.
• Protocol: Animal Study ^[7]
• Animal Models: Male Sprague-Dawley rats with approximately 5/6 renal ablation
• Formulation: Dissolved in DMSO, and diluted in saline
• Doses: 1 g/kg/day
• Administration: Orally

References

• References: [1] Johnson JD, et al. J Pharmacol Exp Ther, 1983, 226(2), 330-334.
• References: [2] Rödler S, et al. J Mol Cell Cardiol, 1995, 27(10), 2295-2302.
• References: [3] Yiu S, et al. J Med Chem, 1996, 39(23), 4576-4582.
• References: [4] Ding Y, et al. Hypertension, 1998, 32(4), 718-723.
• References: [5] Yang Z, et al. Cardiovasc Res, 2002, 53(1), 227-231.
• References: [6] Perez-Reyes E, et al. J Pharmacol Exp Ther, 2009, 328(2), 621-627.

Sigma Aldrich - F9677

Biochem/physiol Actions
L-type calcium channel blocker

Toronto Research Chemicals - F232375

A dihydropyridine calcium channel blocker.

参考文献

• Dunselman PH, Edgar B: Felodipine clinical pharmacokinetics. Clin Pharmacokinet. 1991 Dec;21(6):418-30. Pubmed
• Johnson JD, et al. J Pharmacol Exp Ther, 1983, 226(2), 330-334.
• Rödler S, et al. J Mol Cell Cardiol, 1995, 27(10), 2295-2302.
• Yiu S, et al. J Med Chem, 1996, 39(23), 4576-4582.
• Ding Y, et al. Hypertension, 1998, 32(4), 718-723.
• Yang Z, et al. Cardiovasc Res, 2002, 53(1), 227-231.
• Perez-Reyes E, et al. J Pharmacol Exp Ther, 2009, 328(2), 621-627.
• Berntsson, P.B., et al.: Acta Pharm. Suec., 18, 221 (1981)
• Kratochwil, N., et al.: Biochem. Pharmacol., 64, 1355 (1981)
• O'Brien, S., et al.: J. Med. Chem., 48, 1287 (1981)
• Castilho, M., et al.: Bioorg. Med. Chem., 14, 516 (1981)