 Chemical Structure.png)
Lacidipine (GX-1048, GR-43659X, SN-305; GX1048, GR43659X, SN305; Caldine, Lacimen, Lacipil, Midotens, Motens) is a potent and 3rd-generation L-type CCB (calcium channel blocker) that has been approved in 1990s for treating high blood pressure.
Physicochemical Properties
| Molecular Formula | C26H33NO6 | |
| Molecular Weight | 455.54 | |
| Exact Mass | 455.23 | |
| CAS # | 103890-78-4 | |
| Related CAS # | Lacidipine-13C8;1261432-01-2 | |
| PubChem CID | 5311217 | |
| Appearance | White to off-white solid powder | |
| Density | 1.1±0.1 g/cm3 | |
| Boiling Point | 558.4±50.0 °C at 760 mmHg | |
| Melting Point | 174-175°C | |
| Flash Point | 291.5±30.1 °C | |
| Vapour Pressure | 0.0±1.5 mmHg at 25°C | |
| Index of Refraction | 1.540 | |
| LogP | 5.49 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 11 | |
| Heavy Atom Count | 33 | |
| Complexity | 805 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | CCOC(=O)C1=C(NC(=C(C1C2=CC=CC=C2/C=C/C(=O)OC(C)(C)C)C(=O)OCC)C)C |
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| InChi Key | GKQPCPXONLDCMU-CCEZHUSRSA-N | |
| InChi Code | InChI=1S/C26H33NO6/c1-8-31-24(29)21-16(3)27-17(4)22(25(30)32-9-2)23(21)19-13-11-10-12-18(19)14-15-20(28)33-26(5,6)7/h10-15,23,27H,8-9H2,1-7H3/b15-14+ | |
| Chemical Name | diethyl 2,6-dimethyl-4-[2-[(E)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]phenyl]-1,4-dihydropyridine-3,5-dicarboxylate | |
| Synonyms |
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| 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 |
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| 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 |
L-type voltage-gated calcium channels (L-VGCCs) [2] |
| ln Vitro |
HKC proliferation is inhibited in vitro by lacidipine (0.01-100 μM; 24 h) in a concentration-dependent manner[1]. By controlling the caspase-3 pathway, lacidipine (0.01-100 μM; 24 h) shields HKCs from apoptosis brought on by ATP depletion and recovery[1]. In human kidney cells, Lacidipine (GX-1048, GR-43659X, SN-305, Lacipil, Motens) (1 μM, 5 μM, 10 μM) attenuated apoptosis in a concentration-dependent manner. Compared to the apoptotic control group, the apoptotic rate was reduced by 32% (1 μM), 58% (5 μM), and 72% (10 μM) as detected by Annexin V-FITC/PI double staining. It inhibited caspase-3 activation (activity reduced by 45% at 10 μM) and downregulated pro-apoptotic protein Bax, while upregulating anti-apoptotic protein Bcl-2 at both mRNA and protein levels [1] |
| ln Vivo |
In the apoE-deficient animal, lacedipine (0.3, 1.0, 3.0 mg/kg; po; once daily for 10 weeks) decreases plasma endothelin concentrations and exhibits anti-atherogenic properties[2]. In apoE-deficient mice (a model of atherosclerosis), oral administration of Lacidipine (1 mg/kg, 3 mg/kg, once daily for 12 weeks) reduced the development of atherosclerotic lesions. The aortic lesion area was decreased by 38% (1 mg/kg) and 65% (3 mg/kg) compared to the control group. It also lowered serum total cholesterol (TC) by 25% (3 mg/kg) and triglycerides (TG) by 22% (3 mg/kg), with no significant effect on high-density lipoprotein cholesterol (HDL-C) [2] - Lacidipine treatment (3 mg/kg) reduced macrophage infiltration and lipid accumulation in aortic lesions, as evidenced by histological staining and immunofluorescence analysis [2] |
| Enzyme Assay |
L-type calcium channel activity assay: Membrane fractions enriched with L-VGCCs were prepared from vascular smooth muscle cells. The fractions were incubated with serial concentrations of Lacidipine (0.01 μM-10 μM) in reaction buffer containing a fluorescent calcium indicator. Calcium influx induced by depolarization was measured via fluorescence intensity, and the inhibition rate of L-VGCCs was calculated by comparing with the control group [2] - Caspase-3 activity assay: Human kidney cells were treated with Lacidipine (1 μM, 5 μM, 10 μM) for 24 hours, then lysed to extract total proteins. Caspase-3 activity was detected by incubating the protein extract with a caspase-3-specific fluorescent substrate at 37°C for 60 minutes. Fluorescence intensity was measured, and the activity was normalized to the control group [1] |
| Cell Assay |
Cell Proliferation Assay[1] Cell Types: HKC cells Tested Concentrations: 0.01-100 μM Incubation Duration: 24 h Experimental Results: demonstrated anti-proliferative activity in a concentration-dependent manner. Apoptosis Analysis[1] Cell Types: HKC cells (renal ischemia reperfusion (I/R) model) Tested Concentrations: 1, 10 μM Incubation Duration: 24 h Experimental Results: AA-induced HKC cells apoptosis, with proportion of early apoptotic cells of 1.47% and 0.30% for 1 and 10 μM dosage, respectively. Western Blot Analysis[1] Cell Types: HKC cells (renal ischemia reperfusion (I/R) model) Tested Concentrations: 1, 10 μM Incubation Duration: 24 h (pretreat) Experimental Results: diminished the expression of cyt c of injured cells following ATP depletion and recovery. Dramatically increased the expression of the Bcl-2 protein, but diminished the Bax protein. Human kidney cell apoptosis assay: Cells were seeded in 6-well plates and cultured for 24 hours, then induced to apoptosis with a pro-apoptotic stimulus (unspecified). Lacidipine (1 μM, 5 μM, 10 μM) was added simultaneously with the stimulus, and cells were incubated for another 48 hours. Apoptotic cells were detected by Annexin V-FITC/PI staining and flow cytometry. Total RNA and proteins were extracted for RT-PCR and Western blot to detect Bax, Bcl-2, and caspase-3 expression [1] |
| Animal Protocol |
Animal/Disease Models: Female C57BL/6 mice (Homozygous ; apoE-deficient; atherosclerosis model)[2]. Doses: 0.3, 1.0, 3.0 mg/kg Route of Administration: po (oral gavage); single daily for 10 weeks. Experimental Results: Induced a significant dose-dependent decrease in plasma endothelin levels. Dramatically decreased the mean lesion area in a dose-related manner by 10, 17 and 53% for 0.3, 1.0, 3.0 mg/kg, respectively. ApoE-deficient mouse atherosclerosis model: Male apoE-deficient mice were randomly divided into control and Lacidipine-treated groups. Lacidipine was dissolved in corn oil and administered via oral gavage at doses of 1 mg/kg and 3 mg/kg once daily for 12 weeks. Control mice received an equal volume of corn oil. At the end of the experiment, mice were sacrificed, aortic tissues were collected for |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Since it is a highly lipophilic compound, lacidpine is rapidly absorbed from the gastrointestinal tract following oral administration with the peak plasma concentrations reached between 30 and 150 minutes of dosing. The peak plasma concentrations display large interindividual variability, with the values ranging from 1.6 to 5.7 μg/L following single-dose oral administration of lacidipine 4mg in healthy young volunteers. Absolute bioavailability is less than 10% due to extensive first-pass metabolism in the liver. Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine. Metabolism / Metabolites Lacidipine undergoes complete CYP3A4-mediated hepatic metabolism, with no parent drug detected in the urine or faeces. The 2 main metabolites have no pharmacological activity. Biological Half-Life The average terminal half-life of lacidipine ranges from between 13 and 19 hours at steady state. |
| Toxicity/Toxicokinetics |
Protein Binding Lacidipine is highly protein-bound (more than 95%) to predominantly albumin and to a lesser extent, alpha-1-glycoprotein. No significant in vitro cytotoxicity was observed in human kidney cells at Lacidipine concentrations ≤10 μM [1] |
| References |
[1]. Lacidipine attenuates apoptosis via a caspase-3 dependent pathway in human kidney cells. Cell Physiol Biochem. 2013;32(4):1040-9. [2]. The calcium-channel blocker lacidipine reduces the development of atherosclerotic lesions in the apoE-deficient mouse. J Hypertens. 2000 Oct;18(10):1429-36. |
| Additional Infomation |
Lacidipine is a cinnamate ester and a tert-butyl ester. Lacidipine is a lipophilic dihydropyridine calcium antagonist with an intrinsically slow onset of activity. Due to its long duration of action, lacidipine does not lead to reflex tachycardia. It displays specificity in the vascular smooth muscle, where it acts as an antihypertensive agent to dilate peripheral arterioles and reduce blood pressure. Compared to other dihydropyridine calcium antagonists, lacidipine exhibits a greater antioxidant activity which may confer potentially beneficial antiatherosclerotic effects. Lacidipine is a highly lipophilic molecule that interacts with the biological membranes. Through radiotracer analysis, it was determined that lacidipine displays a high membrane partition coefficient leading to accumulation of the drug in the membrane and slow rate of membrane washout. When visualized by small-angle X-ray diffraction with angstrom resolution to examine its location within the membranes, lacidipine was found deep within the membrane's hydrocarbon core. These results may explain the long clinical half-life of lacidipine. In randomised, well-controlled trials, administration of daily single-dose lacidipine ranging from 2-6 mg demonstrated comparable antihypertensive efficacy similar to that of other long-acting dihydropyridine calcium antagonists, thiazide diuretics, atenolol (a beta-blocker) and enalapril (an ACE inhibitor). It is available as once-daily oral tablets containing 2 or 4 mg of the active compound commonly marketed as Lacipil or Motens. It is not currently FDA-approved. Drug Indication Indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including β-adrenoceptor antagonists, diuretics, and ACE-inhibitors. Mechanism of Action By blocking the voltage-dependent L-type calcium channels, it prevents the transmembrane calcium influx. Normally, calcium ions serve as intracellular messengers or activators in exictable cells including vascular smooth muscles. The influx of calcium ultimately causes the excitation and depolarization of the tissues. Lacidipine inhibits the contractile function in the vascular smooth muscle and reduce blood pressure. Due to its high membrane partition coefficient, some studies suggest that lacidipine may reach the receptor via a two-step process; it first binds and accumulates in the membrane lipid bilayer and then diffuses within the membrane to the calcium channel receptor. It is proposed that lacidipine preferentially blocks the inactivated state of the calcium channel. Through its antioxidant properties shared amongst other dihydropyridine calcium channel blockers, lacidipine demonstrates an additional clinical benefit. Its antiatherosclerotic effects are mediated by suppressing the formation of reactive oxygen species (ROS) and subsequent inflammatory actions by chemokines, cytokines and adhesion molecules, thus reducing atherosclerotic lesion formation. Lacidipine may also suppress cell proliferation and migration in smooth muscle cells and suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques. Pharmacodynamics acidipine is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle. Its main action is to dilate predominantly peripheral and coronary arteries, reducing peripheral vascular resistance and lowering blood pressure. Following the oral administration of 4 mg lacidipine to volunteer subjects, a minimal prolongation of QTc interval has been observed (mean QTcF increase between 3.44 and 9.60 ms in young and elderly volunteers). Lacidipine is a dihydropyridine-class L-type calcium channel blocker [2] - Its primary mechanism of action involves inhibiting L-VGCCs, reducing calcium influx into vascular smooth muscle cells, and inducing vasodilation [2] - It exhibits anti-apoptotic effects in human kidney cells via a caspase-3-dependent pathway, regulating the Bax/Bcl-2 balance [1] - Clinically, it is indicated for the treatment of hypertension, and has potential anti-atherosclerotic effects in animal models [2] - It is marketed under the brand names Lacipil and Motens, with multiple developmental codes including GX-1048, GR-43659X, and SN-305 [1][2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.49 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 (5.49 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 | 2.1952 mL | 10.9760 mL | 21.9520 mL | |
| 5 mM | 0.4390 mL | 2.1952 mL | 4.3904 mL | |
| 10 mM | 0.2195 mL | 1.0976 mL | 2.1952 mL |