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Cilnidipine (formerly also known as FRC-8653; FRC8653; Atelec; Cinalong; Siscard) is a novel, potent and unique dual L-type and N-type calcium channel blocker (CCB) that was approved as an anti-hypertensive drug in 1995 for high blood pressure treatment. Cilnidipine lowers mean blood pressure and reduces the size of cerebral infarction in the rat model of focal brain ischemia. Cilnidipine has displayed renal and vascular protective effects and improved baroreflex sensitivity in patients with hypertension. It has also demonstrated neuroprotective effects in a rat focal brain ischemia model by removing free radicals and activating the phosphatidylinositol 3-kinase pathway.
Physicochemical Properties
| Molecular Formula | C27H28N2O7 | |
| Molecular Weight | 492.52 | |
| Exact Mass | 492.189 | |
| CAS # | 132203-70-4 | |
| Related CAS # | Cilnidipine-d7 | |
| PubChem CID | 5282138 | |
| Appearance | Light yellow to green yellow solid powder | |
| Density | 1.2±0.1 g/cm3 | |
| Boiling Point | 652.6±55.0 °C at 760 mmHg | |
| Melting Point | 97-99°C | |
| Flash Point | 348.5±31.5 °C | |
| Vapour Pressure | 0.0±2.0 mmHg at 25°C | |
| Index of Refraction | 1.592 | |
| LogP | 5.36 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 8 | |
| Rotatable Bond Count | 11 | |
| Heavy Atom Count | 36 | |
| Complexity | 896 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | CC1=C(C(C(=C(N1)C)C(=O)OC/C=C/C2=CC=CC=C2)C3=CC(=CC=C3)[N+](=O)[O-])C(=O)OCCOC |
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| InChi Key | KJEBULYHNRNJTE-DHZHZOJOSA-N | |
| InChi Code | InChI=1S/C27H28N2O7/c1-18-23(26(30)35-14-8-11-20-9-5-4-6-10-20)25(21-12-7-13-22(17-21)29(32)33)24(19(2)28-18)27(31)36-16-15-34-3/h4-13,17,25,28H,14-16H2,1-3H3/b11-8+ | |
| Chemical Name | 3-O-(2-methoxyethyl) 5-O-[(E)-3-phenylprop-2-enyl] 2,6-dimethyl-4-(3-nitrophenyl)-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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
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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 |
N-type Ca2+ channel (rat dorsal root ganglion neurons), [1] - Vascular L-type calcium channels [2] - Phosphatidylinositol 3-kinase (PI3K) pathway (involved in neuroprotective effect), [3] |
| ln Vitro |
In neurons pretreated with omegaCgTx plus omegaAgTx, celidipine inhibits the L-type current with an IC50 of 100 nM[1]. Cilnidipine's IC50 with regard to the N-type current is 200 nM[1]. With an IC50 of 10 nM at 10 min, clinidipine dose- and time-dependently inhibits the contractions of rat aortic rings caused by depolarization and Ca2+[2]. When exposed to more than 200 μM of Cilnidipine, the viability of nPC12 cells decreases slightly, but does not change significantly up to 150 μM of the drug[3]. After two hours of treatment at 100 μM, cilnidipine increases the expression of p85aPI3K, p-Akt, p-GSK-3β, and heat shock transcription factor (HSTF-1), while cytosolic cytochrome c, activated caspase 3, and cleaved PARP levels decrease[3]. In rat dorsal root ganglion neurons, Cilnidipine inhibited N-type Ca2+ channel currents in a concentration-dependent manner, with significant suppression observed at relevant concentrations without complete blockage [1] - In vascular smooth muscle-related in vitro models, Cilnidipine acted as a slow-acting blocker of L-type calcium channels, exerting inhibitory effects on channel activity independent of protein kinase C (PKC) targeting [2] - In neuronal cells subjected to oxidative stress, Cilnidipine scavenged free radicals, reduced oxidative damage, and activated the PI3K pathway, thereby enhancing neuronal survival and exerting neuroprotective effects [3] |
| ln Vivo |
In rat dorsal root ganglion neurons, cilnidipine has strong inhibitory effects on both L-type and N-type voltage-dependent Ca2+ channels[1]. The use of 10 mg/kg of cilnidipine and 10 mg/kg of nicodipine greatly reduces the behavioral abnormalities brought on by immobilization stress, restores deficit memories, and normalizes corticosterone levels[4]. Both nicodipine and clonidipine have similar positive effects on immobilized mice under stress[4]. In 2K1C renal hypertensive dogs, oral Cilnidipine (3 mg/kg) significantly reduces both systolic and diastolic blood pressure one hour after administration[5]. In 2K1C renal hypertensive dogs, repeated oral administration of Cilnidipine produced significant antihypertensive effects, effectively reducing elevated blood pressure [5] - In immobilization-stressed mice, Cilnidipine exhibited anti-stress effects, as evidenced by modulation of stress-related physiological parameters and behaviors compared to control groups [4] |
| Enzyme Assay |
For N-type Ca2+ channel activity assay: Isolated rat dorsal root ganglion neurons were used, and Ca2+ channel currents were recorded using patch-clamp technique. Cilnidipine was applied at different concentrations, and current changes were measured to evaluate inhibitory effects [1] - For L-type calcium channel activity assay: Vascular tissue-derived preparations were used to assess channel function. Cilnidipine was incubated with the preparations, and changes in L-type Ca2+ channel activity were detected to determine blocking efficiency, with PKC activity also measured to confirm non-targeting effect [2] |
| Cell Assay |
Cell Viability Assay Cell Types: Neuronally differentiated PC12 (nPC12) cells Tested Concentrations: 0, 1, 5, 10, 25, 50, 100, 150, and 200 μM Incubation Duration: Treated for 2 hrs (hours); cell viability was measured after 24 hrs (hours) Experimental Results: Cell viability was not affected by low concentrations up to 150 μM, but it was slightly diminished at 200 μM. Western Blot Analysis Cell Types: nPC12 cells Tested Concentrations: 100 μM Incubation Duration: 2 hrs (hours) Experimental Results: Increased the IRs of p58a PI3K, p-Akt, p-GSK-3β, and HSTF-1 and diminished the Immunoreactivities (IRs) of cytosolic cytochrome c, activated caspase 3 (17 kDa), and cleaved PARP (85 kDa). For neuronal cell oxidative stress assay: Neuronal cells were exposed to oxidative stressors, and Cilnidipine was added at specific concentrations. Free radical levels were detected, and PI3K pathway-related protein expression was analyzed to evaluate neuroprotective mechanisms [3] - For dorsal root ganglion neuron assay: Rat dorsal root ganglion neurons were cultured and patched using whole-cell patch-clamp method. Cilnidipine was administered via bath application, and N-type Ca2+ channel current amplitudes were recorded and analyzed [1] |
| Animal Protocol |
Animal/Disease Models: Swiss albino mice weighing 25±5 g[4] Doses: 5 and 10 mg/kg Route of Administration: administered ip 30 min prior to immobilization stress Experimental Results: Cilnidipine (10 mg/kg, ip) and nimodipine (10 mg/kg, ip) 30 min prior to subjecting immobilization stress resulted in significant attenuation of immobilization stress-induced decrease in locomotor activity. Administration with Cilnidipine (5 mg /kg, ip) and Nimodipine (5 mg/kg, ip) did not show any significant effect on the stressed mice. Administration of Cilnidipine (10 mg/kg, ip) and Nimodipine (10 mg/kg, ip) in the non -stressed mice, and vehicle in the stressed mice did not modulate locomotor activity in a significant manner. For 2K1C renal hypertensive dogs: Dogs were induced to develop renal hypertension via the 2K1C method. Cilnidipine was prepared as an oral formulation, administered repeatedly at specified doses, and blood pressure was measured at regular intervals to assess antihypertensive efficacy [5] - For immobilization-stressed mice: Mice were subjected to immobilization stress. Cilnidipine was administered via an appropriate route (not specified in public data) at specific doses, and stress-related indicators (physiological and behavioral) were evaluated after treatment [4] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Cilnidipine presents a very rapid absorption with a maximum peaked concentration after 2 hours. Its distribution tends to be higher in the liver as well as in kidneys, plasma and other tissues. Cilnidipine does not present a high accumulation in the tissue after repeated oral administration. Cilnidipine is reported to present very low bioavailability determined to be approximately 13%. This low bioavailability is suggested to be due to its low aqueous solubility and high permeability. Hence, efforts have been made in order to find an innovative formulation that can significantly improve the bioavailability of this drug. One of these formulations corresponds to the generation of polymeric nanoparticles which enhance the bioavailability by 2.5-3-fold. Cilnidipine gets eliminated through the urine in a proportion of 20% of the administered dose and 80% is eliminated by the feces. Drugs on the group of dihydropyridines such as cilnidipine tend to have a large volume of distribution. Metabolism / Metabolites Cilnidipine is metabolized by both liver and kidney. It is rapidly metabolized by liver microsomes by a dehydrogenation process. The major enzymatic isoform involved in cilnidipine dehydrogenation of the dihydropyridine ring is CYP3A. Biological Half-Life The half-life of the hypotensive effect for cilnidipine is of about 20.4 min. |
| Toxicity/Toxicokinetics |
Protein Binding Cilnidipine presents a very high protein binding that represents to even 98% of the administered dose. |
| References |
[1]. Effect of cilnidipine, a novel dihydropyridine Ca2+-channel antagonist, on N-type Ca2+ channel in rat dorsal root ganglion neurons. J Pharmacol Exp Ther. 1997 Mar;280(3):1184-91. [2]. Cilnidipine is a novel slow-acting blocker of vascular L-type calcium channels that does not target protein kinase C. J Hypertens. 2002 May;20(5):885-93. [3]. Cilnidipine mediates a neuroprotective effect by scavenging free radicals and activating the phosphatidylinositol 3-kinase pathway. J Neurochem. 2009 Oct;111(1):90-100. [4]. Anti-stress effects of cilnidipine and nimodipine in immobilization subjected mice. Physiol Behav. 2012 Mar 20;105(5):1148-55. [5]. [Antihypertensive effects of repeated oral administration of cilnidipine, a novel calcium antagonist, in 2K1C renal hypertensive dogs]. Nihon Yakurigaku Zasshi. 1995 Oct;106(4):279-87. |
| Additional Infomation |
Cilnidipine is a diesterified 1,4-dihydropyridine-3,5-dicarboxylic acid. A calcium channel blocker, it is used as an antihypertensive. It has a role as a calcium channel blocker, an antihypertensive agent and a cardiovascular drug. It is a dihydropyridine, a 2-methoxyethyl ester and a C-nitro compound. Cilnidipine is a dihydropyridine calcium antagonist. It was jointly developed by Fuji Viscera Pharmaceutical Company, Japan and Ajinomoto, Japan and approved in 1995. Compared with other calcium antagonists, cilnidipine can act on the N-type calcium channel that existing sympathetic nerve end besides acting on L-type calcium channel that similar to most of the calcium antagonists. This drug is approved in China, Japan, Korea, India, and several countries in the European Union. Drug Indication Cilnidipine is indicated for the management of hypertension for end-organ protection. It is reported to be useful in elderly patients and in those with diabetes and albuminuria. Cilnidipine has been increasingly used in patients with chronic kidney disease Hypertension is the term used to describe the presence of high blood pressure. The blood pressure is generated by the force of the blood pumped from the heart against the blood vessels. Thus hypertension is caused when there is too much pressure on the blood vessels and this effect can damage the blood vessel. Mechanism of Action Cilnidipine acts on the L-type calcium channels of blood vessels by blocking the incoming calcium and suppressing the contraction of blood vessels, thereby reducing blood pressure. Cilnidipine also works on the N-type calcium channel located at the end of the sympathetic nerve, inhibiting the emission of norepinephrine and suppressing the increase in stress blood pressure. Pharmacodynamics Administration of cilnidipine has been shown to present an antisympathetic profile in vitro and in vivo. It decreases blood pressure safely and effectively without excessive blood pressure reduction or tachycardia. Cilnidipine is a novel dihydropyridine Ca2+-channel antagonist with dual effects on N-type and L-type calcium channels [1][2] - The neuroprotective effect of Cilnidipine is closely associated with free radical scavenging and PI3K pathway activation, providing a potential therapeutic target for neuronal injury [3] - Compared with nimodipine, Cilnidipine shows comparable anti-stress effects in immobilized mice, indicating its potential in stress-related disorders [4] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.08 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 (5.08 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. Solubility in Formulation 3: 5% DMSO +Corn oil : 7 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0304 mL | 10.1519 mL | 20.3037 mL | |
| 5 mM | 0.4061 mL | 2.0304 mL | 4.0607 mL | |
| 10 mM | 0.2030 mL | 1.0152 mL | 2.0304 mL |