Lemildipine targets voltage-gated L-type calcium channels, which are expressed in the cardiovascular system and are responsible for the influx of calcium into cells during depolarization. By blocking these channels, Lemildipine reduces the intracellular calcium concentration in vascular smooth muscle cells, leading to vasodilation and a decrease in peripheral vascular resistance. The compound's calcium channel blocking activity is stereoselective, with different enantiomers exhibiting different potencies in vascular tissues. In addition to its effects on L-type calcium channels, Lemildipine has been shown to dilate afferent arterioles in the kidney, which may contribute to its antihypertensive effects by modulating renal hemodynamics and the tubuloglomerular feedback mechanism.

In vitro, Lemildipine exhibits potent calcium antagonistic activity in various vascular preparations. The compound inhibits potassium-induced contractions in isolated vascular strips in a concentration-dependent manner. Its inhibitory effects are more potent in certain vascular beds, such as the coronary and cerebral arteries, compared to other vascular tissues. The compound's stereoselective properties have been demonstrated in binding studies using radiolabeled calcium channel ligands, showing that different enantiomers of Lemildipine have different affinities for the calcium channel binding site. Lemildipine also attenuates the tubuloglomerular feedback response in renal microperfusion studies, indicating its ability to modulate renal function.

After the blockage is released, give gerbils intraperitoneal lemildipine (0.1-3 mg/kg) treatment. After four days of ischemia, they were perfused with 10% buffered formalin to fix them, and a microscope was used to measure the neuronal cell density (NCD, cells/mm) in the CA1 sector. The ischemia control group had a mean NCD of 43±10.8 cells/mm3, whereas lemildipine (3 mg/kg) dramatically increased DND to 143±24.2 cells/mm (P<0.01). Additionally, after 1–2–4 weeks of transient ischemia, Lemildipine (3 mg/kg) significantly reduced delayed neuronal death (DND). The average NCD in the Lemildipine group was 80±9.4 (P<0.01) and 43 were ±7.7 cells/mm, 92±13.7 (P<0.05) and 52±9.3 cells/mm, and 57±5.0 (P<0.01) and 43±12.4 cells/mm, respectively. Lemildipine (NB-818) was found to have a protective impact on DND in the hippocampus CA1 subregion following acute forebrain ischemia [1]. This effect persisted for a maximum of four weeks. Lemildipine (NPK-1886) at oral dosages of 3–30 mg/kg caused moderate decreases in blood pressure in normal Wistar rats (NWR). Remidipine and nifedipine have extremely comparable antihypertensive effects. On the other hand, lemildipine markedly lowered blood pressure in rats that were spontaneously hypertensive (SHR). A dose-dependent, statistically significant decrease in systolic blood pressure was observed upon oral administration of lemildipine at dosages of 3, 10, and 30 mg/kg. The greatest reduction was noticed one to three hours after medication. The dose-response curve at the maximal response during the course of the observation period (24 hours) was evaluated using the least squares approach in order to compare the antihypertensive efficacy of remidipine with nifedipine. Its potency was determined by calculating the dose that caused a 30% drop in blood pressure when compared to the control level (ED30). The ED30 values of remidipine and nifedipine are 10.2 mg/kg and 14.3 mg/kg, respectively; remidipine is 1.4 times more powerful than nifedipine [2].

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In vivo, Lemildipine has been shown to lower blood pressure in animal models of hypertension, including spontaneously hypertensive rats (SHR). The compound's antihypertensive effects are attributed to its vasodilatory activity and its ability to reduce peripheral vascular resistance. In SHR, Lemildipine attenuates the TGF response by dilating afferent arterioles, which corrects the leftward and downward shift of the TGF curve characteristic of this hypertensive model. This effect on renal hemodynamics may contribute to the compound's blood pressure-lowering effects and its potential to protect against hypertensive nephropathy. The compound has also been studied for its cerebrovascular effects, showing vasodilatory activity in dog cerebral arteries.

The non-cellular assay for Lemildipine involves radioligand binding to membrane preparations from tissues expressing L-type calcium channels. Membranes are incubated with a fixed concentration of a radiolabeled calcium channel ligand (such as [³H]-nitrendipine or [³H]-PN200-110) and varying concentrations of Lemildipine. After incubation, bound and free radioligand are separated by filtration, and radioactivity is measured by liquid scintillation counting. The binding affinity (Ki or IC50) of Lemildipine for the calcium channel is determined from competition curves. The stereoselectivity of the compound's binding is assessed by testing the individual enantiomers. In functional assays, the inhibition of potassium-induced contractions in isolated vascular strips is used to assess the compound's calcium antagonistic activity. The compound is added cumulatively to pre-contracted tissues, and the relaxation response is measured isometrically.

The cellular assay for Lemildipine involves measuring calcium influx in cultured vascular smooth muscle cells or other cell types expressing L-type calcium channels. Cells are loaded with a calcium-sensitive fluorescent dye (such as Fura-2 or Fluo-4) and stimulated with a depolarizing agent (such as potassium chloride) to induce calcium influx. Lemildipine is added prior to or during the stimulation, and the reduction in the calcium signal is measured using fluorescence microscopy or a fluorescence plate reader. The IC50 for calcium channel blockade is determined from concentration-response curves. In addition to calcium imaging, the effects of Lemildipine on cell proliferation and migration can be studied, as calcium signaling is involved in these processes. Cytotoxicity is assessed using standard cell viability assays.

The in vivo animal studies for Lemildipine typically use spontaneously hypertensive rats (SHR) or other hypertensive models. Blood pressure is measured by tail-cuff plethysmography or telemetry before and after administration of the compound. Lemildipine is administered orally or intravenously at various doses, and the time course of blood pressure reduction is monitored. In renal function studies, the tubuloglomerular feedback response is assessed by micropuncture or by measuring renal blood flow and glomerular filtration rate. The effects of Lemildipine on renal hemodynamics are compared to those of other calcium channel blockers. In cerebrovascular studies, the compound's effects on cerebral blood flow are assessed using laser Doppler flowmetry or other techniques. The compound's tissue selectivity is evaluated by comparing its effects in different vascular beds.

Lemildipine has a molecular weight of 457.30 g/mol and a molecular formula of C₂₀H₂₂Cl₂N₂O₆. The compound is a dihydropyridine derivative with a lipophilic character, which is typical of this class of calcium channel blockers. Its pharmacokinetic properties, including oral bioavailability, half-life, and tissue distribution, have been characterized in preclinical species. As a dihydropyridine calcium channel blocker, Lemildipine is expected to have good oral absorption and extensive hepatic metabolism, similar to other drugs in this class. The compound's stereoselective pharmacokinetics have also been studied, as different enantiomers may have different rates of metabolism and elimination.

Lemildipine is generally well-tolerated in preclinical studies at therapeutically relevant doses. However, as a calcium channel blocker, it may cause dose-dependent side effects such as hypotension, reflex tachycardia, and peripheral edema, which are common to this class of compounds. The compound's safety profile is consistent with that of other dihydropyridine calcium channel blockers. Long-term toxicity studies and genotoxicity assays have not been reported in the available literature. Lemildipine is not approved for clinical use and is primarily a research compound.

[1]. Effect of a new calcium entry blocker, NB-818, on delayed neuronal death in the ischemic gerbil hippocampus. Jpn J Pharmacol. 1991 Jul;56(3):279-86.

[2]. Cardiovascular effects of NPK-1886, a new dihydropyridine compound with calcium entry blocking activity. Jpn J Pharmacol. 1986 Mar;40(3):399-409.

Lemildipine is a dihydropyridine compound that has properties similar to both isopropyl and methyl esters.

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Lemildipine is a new dihydropyridine calcium channel blocker that has been studied for its potential in the treatment of hypertension. Its unique features include stereoselective calcium antagonistic properties and tissue selectivity, with particular activity in the coronary and cerebral vasculatures. The compound's ability to attenuate the tubuloglomerular feedback response in hypertensive models suggests potential renoprotective effects. Lemildipine continues to be of interest for cardiovascular research and as a lead compound for the development of new calcium channel blockers with improved selectivity and safety profiles.

C20H22CL2N2O6

457.304

456.085

94739-29-4

65953

White to yellow solid powder

1.335±0.06 g/cm3 (20 °C, 760 mmHg)

585.6±50.0 °C (760 mmHg)

4.457

2

7

9

30

764

0

WTOVRSWDBLIFHU-UHFFFAOYSA-N

InChI=1S/C20H22Cl2N2O6/c1-9(2)30-19(26)16-13(8-29-20(23)27)24-10(3)14(18(25)28-4)15(16)11-6-5-7-12(21)17(11)22/h5-7,9,15,24H,8H2,1-4H3,(H2,23,27)

5-O-methyl 3-O-propan-2-yl 2-(carbamoyloxymethyl)-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate

NB-818NPK-1886NPK 1886NB 818 NB818 NPK1886

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~218.67 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.47 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.47 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.

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 (Please use freshly prepared in vivo formulations for optimal results.)