Identification

Name
Nilvadipine
Accession Number
DB06712
Type
Small Molecule
Groups
Investigational
Description

Nilvadipine is a calcium channel blocker (CCB) for treatment of hypertension.

Structure
Thumb
Synonyms
  • Nivadil
International/Other Brands
Nivadil
Categories
UNII
0214FUT37J
CAS number
75530-68-6
Weight
Average: 385.3707
Monoisotopic: 385.127385355
Chemical Formula
C19H19N3O6
InChI Key
FAIIFDPAEUKBEP-UHFFFAOYSA-N
InChI
InChI=1S/C19H19N3O6/c1-10(2)28-19(24)15-11(3)21-14(9-20)17(18(23)27-4)16(15)12-6-5-7-13(8-12)22(25)26/h5-8,10,16,21H,1-4H3
IUPAC Name
3-methyl 5-propan-2-yl 2-cyano-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
SMILES
COC(=O)C1=C(NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC(C)C)C#N

Pharmacology

Indication

For the management of vasospastic angina, chronic stable angina and hypertension.

Pharmacodynamics

Nilvadipine is similar to other dihydropyridines including amlodipine, felodipine, isradipine, and nicardipine. Nilvadipine is used to treat Prinzmetal's angina, hypertension, and other vascular disorders such as Raynaud's phenomenon. By blocking the calcium channels, Nifedipine inhibits the spasm of the coronary artery and dilates the systemic arteries, results in a increase of myocardial oxygen supply and a decrease in systemic blood pressure.

Mechanism of action

Nilvadipine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of 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.

TargetActionsOrganism
AVoltage-dependent L-type calcium channel subunit alpha-1C
inhibitor
Human
AVoltage-dependent calcium channel subunit alpha-2/delta-1
inhibitor
Human
AVoltage-dependent L-type calcium channel subunit beta-2
inhibitor
Human
UVoltage-dependent L-type calcium channel subunit alpha-1D
inhibitor
Human
UVoltage-dependent L-type calcium channel subunit alpha-1S
inhibitor
Human
UVoltage-dependent calcium channel subunit alpha-2/delta-3
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Nilvadipine.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Nilvadipine.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Nilvadipine is combined with 2,4-thiazolidinedione.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Nilvadipine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Nilvadipine.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Nilvadipine.
6-Deoxyerythronolide BThe metabolism of Nilvadipine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Nilvadipine.
AbafunginThe therapeutic efficacy of Abafungin can be increased when used in combination with Nilvadipine.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Nilvadipine.
Food Interactions
  • Take without regard to meals

References

Synthesis Reference

Minoru Nakano, Toshinobu Uemura, Shinichi Morizane, Kiyoshi Okuda, Keiko Nakata, "Method of producing a solid dispersion of the sparingly water-soluble drug, nilvadipine." U.S. Patent US5340591, issued March, 1985.

US5340591
General References
Not Available
External Links
Human Metabolome Database
HMDB0015657
KEGG Drug
D01908
PubChem Compound
4494
PubChem Substance
99443264
ChemSpider
4338
BindingDB
50017328
ChEBI
31911
ChEMBL
CHEMBL517427
PharmGKB
PA165958385
Wikipedia
Nilvadipine
ATC Codes
C08CA10 — Nilvadipine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAlzheimer's Disease (AD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0124 mg/mLALOGPS
logP2.97ALOGPS
logP2.24ChemAxon
logS-4.5ALOGPS
pKa (Strongest Basic)-0.57ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area134.24 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity101.8 m3·mol-1ChemAxon
Polarizability37.54 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9377
Blood Brain Barrier-0.9749
Caco-2 permeable+0.6864
P-glycoprotein substrateSubstrate0.5516
P-glycoprotein inhibitor IInhibitor0.915
P-glycoprotein inhibitor IIInhibitor0.9125
Renal organic cation transporterNon-inhibitor0.9071
CYP450 2C9 substrateNon-substrate0.8306
CYP450 2D6 substrateNon-substrate0.8932
CYP450 3A4 substrateSubstrate0.7268
CYP450 1A2 substrateInhibitor0.7753
CYP450 2C9 inhibitorInhibitor0.5318
CYP450 2D6 inhibitorNon-inhibitor0.9291
CYP450 2C19 inhibitorInhibitor0.6042
CYP450 3A4 inhibitorInhibitor0.6375
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8599
Ames testNon AMES toxic0.6114
CarcinogenicityNon-carcinogens0.5194
BiodegradationNot ready biodegradable0.995
Rat acute toxicity2.5335 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7842
hERG inhibition (predictor II)Non-inhibitor0.8944
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-0179000000-b1d9dd06d2542abddd3c

Taxonomy

Description
This compound belongs to the class of organic compounds known as dihydropyridinecarboxylic acids and derivatives. These are compounds containing a dihydropyridine moiety bearing a carboxylic acid group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Hydropyridines
Direct Parent
Dihydropyridinecarboxylic acids and derivatives
Alternative Parents
Nitrobenzenes / Nitroaromatic compounds / Dicarboxylic acids and derivatives / Vinylogous amides / Enoate esters / Methyl esters / Amino acids and derivatives / Propargyl-type 1,3-dipolar organic compounds / Nitriles / Azacyclic compounds
show 7 more
Substituents
Dihydropyridinecarboxylic acid derivative / Nitrobenzene / Nitroaromatic compound / Monocyclic benzene moiety / Dicarboxylic acid or derivatives / Benzenoid / Vinylogous amide / Methyl ester / Enoate ester / Alpha,beta-unsaturated carboxylic ester
show 25 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1C
Uniprot ID
Q13936
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1C
Molecular Weight
248974.1 Da
References
  1. Rosenthal J: Nilvadipine: profile of a new calcium antagonist. An overview. J Cardiovasc Pharmacol. 1994;24 Suppl 2:S92-107. [PubMed:7898101]
  2. Morel N, Buryi V, Feron O, Gomez JP, Christen MO, Godfraind T: The action of calcium channel blockers on recombinant L-type calcium channel alpha1-subunits. Br J Pharmacol. 1998 Nov;125(5):1005-12. [PubMed:9846638]
  3. Striessnig, J. (2004). Ca 2+ channel blockers. In Encyclopedic reference of molecular pharmacology (pp. 201-207). Berlin: Springer. [ISBN:9783540298328]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-...
Gene Name
CACNA2D1
Uniprot ID
P54289
Uniprot Name
Voltage-dependent calcium channel subunit alpha-2/delta-1
Molecular Weight
124566.93 Da
References
  1. Li GR, Deng XL, Sun H, Chung SS, Tse HF, Lau CP: Ion channels in mesenchymal stem cells from rat bone marrow. Stem Cells. 2006 Jun;24(6):1519-28. Epub 2006 Feb 16. [PubMed:16484345]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  3. Araie M, Mayama C: Use of calcium channel blockers for glaucoma. Prog Retin Eye Res. 2011 Jan;30(1):54-71. doi: 10.1016/j.preteyeres.2010.09.002. Epub 2010 Oct 8. [PubMed:20933604]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and ina...
Gene Name
CACNB2
Uniprot ID
Q08289
Uniprot Name
Voltage-dependent L-type calcium channel subunit beta-2
Molecular Weight
73579.925 Da
References
  1. Rosenthal J: Nilvadipine: profile of a new calcium antagonist. An overview. J Cardiovasc Pharmacol. 1994;24 Suppl 2:S92-107. [PubMed:7898101]
  2. Honerjager P, Seibel K: Pharmacodynamics of nilvadipine, a new dihydropyridine-type calcium antagonist. J Cardiovasc Pharmacol. 1992;20 Suppl 6:S15-21. [PubMed:1283184]
  3. Araie M, Mayama C: Use of calcium channel blockers for glaucoma. Prog Retin Eye Res. 2011 Jan;30(1):54-71. doi: 10.1016/j.preteyeres.2010.09.002. Epub 2010 Oct 8. [PubMed:20933604]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity involved sa node cell action potential
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1D
Uniprot ID
Q01668
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1D
Molecular Weight
245138.75 Da
References
  1. Sinnegger-Brauns MJ, Huber IG, Koschak A, Wild C, Obermair GJ, Einzinger U, Hoda JC, Sartori SB, Striessnig J: Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. Mol Pharmacol. 2009 Feb;75(2):407-14. doi: 10.1124/mol.108.049981. Epub 2008 Nov 24. [PubMed:19029287]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1S
Uniprot ID
Q13698
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1S
Molecular Weight
212348.1 Da
References
  1. Peterson BZ, Catterall WA: Allosteric interactions required for high-affinity binding of dihydropyridine antagonists to Ca(V)1.1 Channels are modulated by calcium in the pore. Mol Pharmacol. 2006 Aug;70(2):667-75. Epub 2006 May 4. [PubMed:16675661]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated ion channel activity
Specific Function
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-t...
Gene Name
CACNA2D3
Uniprot ID
Q8IZS8
Uniprot Name
Voltage-dependent calcium channel subunit alpha-2/delta-3
Molecular Weight
123010.22 Da
References
  1. Furukawa T, Nukada T, Suzuki K, Fujita Y, Mori Y, Nishimura M, Yamanaka M: Voltage and pH dependent block of cloned N-type Ca2+ channels by amlodipine. Br J Pharmacol. 1997 Jul;121(6):1136-40. [PubMed:9249249]
  2. Furukawa T, Yamakawa T, Midera T, Sagawa T, Mori Y, Nukada T: Selectivities of dihydropyridine derivatives in blocking Ca(2+) channel subtypes expressed in Xenopus oocytes. J Pharmacol Exp Ther. 1999 Nov;291(2):464-73. [PubMed:10525060]
  3. Miyashita Y, Furukawa T, Kamegaya E, Yoshii M, Nukada T: A region of N-type Ca(2+) channel critical for blockade by the dihydropyridine amlodipine. Eur J Pharmacol. 2010 Apr 25;632(1-3):14-22. doi: 10.1016/j.ejphar.2010.01.006. Epub 2010 Jan 22. [PubMed:20097194]
  4. Murakami M, Nakagawasai O, Fujii S, Kameyama K, Murakami S, Hozumi S, Esashi A, Taniguchi R, Yanagisawa T, Tan-no K, Tadano T, Kitamura K, Kisara K: Antinociceptive action of amlodipine blocking N-type Ca2+ channels at the primary afferent neurons in mice. Eur J Pharmacol. 2001 May 11;419(2-3):175-81. [PubMed:11426839]
  5. Ogihara T, Kano T, Kakinuma C: Evaluation of the inhibitory effect of dihydropyridines on N-type calcium channel by virtual three-dimensional pharmacophore modeling. Arzneimittelforschung. 2009;59(6):283-8. doi: 10.1055/s-0031-1296398. [PubMed:19634509]
  6. Qu YL, Sugiyama K, Ohnuki T, Hattori K, Watanabe K, Nagatomo T: Comparison of binding affinities of omega-conotoxin and amlodipine to N-type Ca2+ channels in rat brain. Zhongguo Yao Li Xue Bao. 1998 Mar;19(2):97-100. [PubMed:10374627]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Niwa T, Shiraga T, Hashimoto T, Kagayama A: Effect of nilvadipine, a dihydropyridine calcium antagonist, on cytochrome P450 activities in human hepatic microsomes. Biol Pharm Bull. 2004 Mar;27(3):415-7. [PubMed:14993813]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Niwa T, Shiraga T, Hashimoto T, Kagayama A: Effect of nilvadipine, a dihydropyridine calcium antagonist, on cytochrome P450 activities in human hepatic microsomes. Biol Pharm Bull. 2004 Mar;27(3):415-7. [PubMed:14993813]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Current data supporting this enzyme inhibition is limited to one in vitro study.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Niwa T, Shiraga T, Hashimoto T, Kagayama A: Effect of nilvadipine, a dihydropyridine calcium antagonist, on cytochrome P450 activities in human hepatic microsomes. Biol Pharm Bull. 2004 Mar;27(3):415-7. [PubMed:14993813]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Niwa T, Shiraga T, Hashimoto T, Kagayama A: Effect of nilvadipine, a dihydropyridine calcium antagonist, on cytochrome P450 activities in human hepatic microsomes. Biol Pharm Bull. 2004 Mar;27(3):415-7. [PubMed:14993813]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Niwa T, Shiraga T, Hashimoto T, Kagayama A: Effect of nilvadipine, a dihydropyridine calcium antagonist, on cytochrome P450 activities in human hepatic microsomes. Biol Pharm Bull. 2004 Mar;27(3):415-7. [PubMed:14993813]

Drug created on May 16, 2010 11:33 / Updated on November 02, 2018 06:19