Nisoldipine
Basic information
- CAS
63675-72-9- Standard SMILES
COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1c1ccccc1[N+](=O)[O-]- InChIKey
VKQFCGNPDRICFG-UHFFFAOYSA-N- Molecular formula
- C20H24N2O6
- Average molar mass
- 388.4 g/mol
- Monoisotopic mass
- 388.16343649
Overview
Methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate is a dihydropyridine that is 1,4-dihydropyridine which is substituted by methyl groups at positions 2 and 6, a methoxycarbonyl group at position 3, an o-nitrophenyl group at position 4, and an isobutoxycarbonyl group at position 5. The racemate, a calcium channel blocker, is used in the treatment of hypertension and angina pectoris. It is a member of dicarboxylic acids and O-substituted derivatives, a methyl ester, a C-nitro compound, a dihydropyridine and a diester.
Names & identifiers
- Preferred name
- Nisoldipine
- IUPAC
- 3-O-methyl 5-O-(2-methylpropyl) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
- English name
- Nisoldipine
- Molecular formula
- C20H24N2O6
- Molecular weight
- 388.41
Names & synonyms
nisoldipine63675-72-9SularNisocorBaymycardNisoldipinBay k 5552NisoldipinoNisoldipinumBay-k-5552Geomatrix 16eDTXSID0023371
Show more names
1,4-DIHYDRO-2,6-DIMETHYL-4-(2-NITROPHENYL)-3,5-PYRIDINEDICARBOXYLIC ACID METHYL 2-METHYLPROPYL ESTERNisoLSyseorSYSCORNORVASCNikamealZADIPINA
Nisoldipine (stn)Nisoldipine SR4I8HAB65SZNSC-7591063,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, methyl 2-methylpropyl esterDTXCID4033713-methyl 5-(2-methylpropyl) 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, methyl 2-methylpropyl ester, (+-)-
Database identifiers
- CAS
63675-72-9- PubChem CID
- 4499
- DTXSID
DTXSID0023371- ChEMBL
CHEMBL1726、CHEMBL3192341、CHEMBL441428- ChEBI
CHEBI:76917- UNII
- 4I8HAB65SZ
- EC Number
- 264-407-7
- Nikkaji
- J19.554E
Properties
Computed structural properties
- XLogP
- 3.3
- Topological polar surface area
- 110 Ų
- Hydrogen bond donors
- 1
- Hydrogen bond acceptors
- 7
- Rotatable bonds
- 7
- Heavy atoms
- 28
- Formal charge
- 0
- Complexity
- 704
Experimental & physicochemical properties
DrugsPharmaceuticals
LogP
3.1
3.59
Solubility5.77e-03 g/L
Human Drugs
Breast Feeding; Lactation; Antihypertensive Agents; Calcium Channel Blockers; Vasodilator Agents;
FDA approved drugs -> Active ingredient
FDA approved drugs -> Active ingredient
Physical DescriptionSolid
Collision Cross Section
195.5 Ų [M+Na]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID0023371]
193.15 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]
187.2 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]
Physicochemical properties
- Melting point
- 147 · 147-148°C
- Boiling point
- 503.3 · 503.3±50.0 °C(Predicted)
- Density
- 1.205 · 1.205±0.06 g/cm3(Predicted)
- storage temp.
- room temp
- solubility
- 10 mg/mL · DMSO: >10mg/mL
- form
- powder
- pka
- 2.67 · 2.67±0.70(Predicted)
- color
- yellow
- Merck
- 14 · 14,6565
- InChI
- 1S/C20H24N2O6/c1-11(2)10-28-20(24)17-13(4)21-12(3)16(19(23)27-5)18(17)14-8-6-7-9-15(14)22(25)26/h6-9,11,18,21H,10H2,1-5H3
- InChIKey
- VKQFCGNPDRICFG-UHFFFAOYSA-N
- SMILES
- COC(=O)C1=C(C)NC(C)=C(C1c2ccccc2[N+]([O-])=O)C(=O)OCC(C)C
- CAS DataBase Reference
- 63675 · 63675-72-9(CAS DataBase Reference)
- FDA UNII
- 4 I8HAB65SZ · 4I8HAB65SZ
- ATC code
- 8 CA07 · C08CA07
- NIST Chemistry Reference
- Nisoldipine(63675-72-9)
- UNSPSC Code
- 41116107 · 41116107
- NACRES
- 77 · NA.77
- Symbol(GHS)
- 7 · GHS07
- Signal word
- Warning
- Hazard statements
- 302 · H302
- Precautionary statements
- 264 · P264-P270-P301+P312-P501
- Hazard Codes
- Xn
- Risk Statements
- 20 · 20/21/22
- Safety Statements
- 36 · 36
- WGK Germany
- 3 · 3
- RTECS
- 7975600 · US7975600
- HS Code
- 2933399090 · 2933399090
- Storage Class
- 11 · 11 - Combustible Solids
- Hazard Classifications
- 4 Oral · Acute Tox. 4 Oral
Safety & regulation
Safety information is for reference only and does not replace the supplier’s Safety Data Sheet (SDS), applicable regulations, or professional assessment.
GHS classification
GHS Classification
Warning
H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
P203, P264, P270, P273, P280, P301+P317, P302+P352, P317, P318, P321, P330, P362+P364, P391, P405, and P501 (click each P-code to see the statement)
Aggregated GHS information provided per 69 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
Hazard information
Hazard Classes and CategoriesAcute Tox. 4 (100%)
Toxicology
Adverse Effects
Though nisoldipine is well-tolerated among patients, the drug does have some side effects mainly associated with its vasodilating property. Common adverse effects associated with nisoldipine include flushing, vasodilation (4%), hypotension, syncope, peripheral edema (7% to 29%,dose-related), headache (22%), dizziness (3% to 10%), and nausea (2%).
Toxicity Summary
Toxicity due to nisoldipine is diagnosed based on clinical status and history. As described above, hypotension with reflex tachycardia can occur when patients take excessive doses of dihydropyridine calcium channel blockers such as nisoldipine. In some severe cases of nisoldipine toxicity, the clinician will note hypotension with bradycardia. Secondary findings of confusion, heart failure, and abnormal ECG changes such as PR prolongation can indicate toxicity. Additionally, hyperglycemia in patients without diabetes can suggest calcium channel blockers poisoning.
Drug Induced Liver Injury
Drug Induced Liver Injury Rank (DILIrank 2.0)
Nisoldipine
Ambiguous-DILI-concern
3
Adverse reactions
DOI:10.1016/j.drudis.2016.02.015
Effects During Pregnancy and Lactation◉ Summary of Use during Lactation
Safety data
- wgk
- 3
- rtecs
- US7975600
- hs_code
- 2933399090
- risk_code
- 20/21/22
- Signal word
- Warning
- Symbol(GHS)
- GHS07
- hazard_code
- Xn
- safety_code
- 36
- Storage Class
- 11 - Combustible Solids
- Hazard statements
- H302
- Hazard Classifications
- Acute Tox. 4 Oral
- Precautionary statements
- P264-P270-P301+P312-P501
Chemistry & industry
Pharmacology
ATC Code
C - Cardiovascular system
QC - Cardiovascular system
Protein Binding99%
Pharmacodynamics
Nisoldipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Nisoldipine is similar to other peripheral vasodilators. Nisoldipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.
Mechanism of Action
By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nisoldipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.
Biological Half-Life7-12 hours
Metabolism/Metabolites
Pre-systemic metabolism in the gut wall, and this metabolism decreases from the proximal to the distal parts of the intestine. Nisoldipine is highly metabolized; 5 major urinary metabolites have been identified. The major biotransformation pathway appears to be the hydroxylation of the isobutyl ester. A hydroxylated derivative of the side chain, present in plasma at concentrations approximately equal to the parent compound, appears to be the only active metabolite and has about 10% of the activity of the parent compound. Cytochrome P450 enzymes are believed to play a major role in the metabolism of nisoldipine. The particular isoenzyme system responsible for its metabolism has not been identified, but other dihydropyridines are metabolized by cytochrome P450 IIIA4.
Nisoldipine has known human metabolites that include 2,6-Dimethyl-5-(2-methylpropoxycarbonyl)-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, 5-O-(1-hydroxy-2-methylpropyl) 3-O-methyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, and Dehydro Nisoldipine.
FDA Pharmacological Classification
4I8HAB65SZ
NISOLDIPINE
Established Pharmacologic Class [EPC] - Dihydropyridine Calcium Channel Blocker
Chemical Structure [CS] - Dihydropyridines
Mechanisms of Action [MoA] - Calcium Channel Antagonists
Physiologic Effects [PE] - Decreased Blood Pressure
MeSH Pharmacological Classification
Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.
A class of drugs that act by selective inhibition of calcium influx through cellular membranes.
Drugs used to cause dilation of the blood vessels.
Absorption, Distribution and Excretion
Relatively well absorbed into the systemic circulation with 87% of the radiolabeled drug recovered in urine and feces. The absolute bioavailability of nisoldipine is about 5%.
Although 60-80% of an oral dose undergoes urinary excretion, only traces of unchanged nisoldipine are found in urine.
Cellular LocationsMembrane
Metabolite PathwaysNisoldipine Action Pathway
Uses & manufacturing
UsesUse (kg; approx.) in Germany (2009): >100
Applications
DescriptionNisoldipine D4 is another long-acting dihydropyridine calcium channel blocker effective in the treatment of hypertension and angina pectoris. It is reported to have little or no cardiodepressive activity and to be more effective than nifedipine in reducing blood pressure in hypertensives. Nisoldipine has also been shown to be effective in the management of congestive heart failure. Reduction in dosage is necessary in patients with hepatic, but not renal impairment.
UsesDihydropyridine calcium channel blocker. Antihypertensive and antianginal
Usesurease inhibitor
UsesLabeled Nisoldipine, intended for use as an internal standard for the quantification of Nisoldipine by GC- or LC-mass spectrometry.
General DescriptionIn vitro studies show that the effects ofnisoldipine, 1,4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylic acid methyl 2-methylpropyl ester(Sular), on contractile processes are selective, with greaterpotency on vascular smooth muscle than on cardiac muscle.Nisoldipine is highly metabolized, with five majormetabolites identified. As with most of the dihydropyridines,the cytochrome P450 (CYP) 3A4 isozyme is mainlyresponsible for the metabolism of nisoldipine. The majorbiotransformation pathway appears to involve the hydroxylationof the isobutyl ester side chain. This particular metabolitehas approximately 10% of the activity of the parentcompound.
Upstream & downstream products
Upstream raw materials
Additional notes
DefinitionChEBI: A dihydropyridine that is 1,4-dihydropyridine which is substituted by methyl groups at positions 2 and 6, a methoxycarbonyl group at position 3, an o-nitrophenyl group at position 4, and an isobutoxycarbonyl group at position 5. The racemate, calcium channel blocker, is used in the treatment of hypertension and angina pectoris.
Related reactions
1 records
Compound notes
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