Nitrendipine is a calcium channel blocker with marked vasodilator action. It is an effective antihypertensive agent and differs from other calcium channel blockers in that it does not reduce glomerular filtration rate and is mildly natriuretic, rather than sodium retentive.

Structure

Similar Structures

Synonyms

1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl methyl ester
Nitrendipine
Nitrendipino
Nitrendipinum

External IDs

BAY E 5009 / BAY-E-5009

International/Other Brands

Bayotensin / Baypress / Bylotensin / Deiten / Nidrel / Nitrepin / Nitrezic

Categories

UNII

9B627AW319

CAS number

39562-70-4

Weight

Average: 360.3612
Monoisotopic: 360.132136382

Chemical Formula

C₁₈H₂₀N₂O₆

InChI Key

PVHUJELLJLJGLN-UHFFFAOYSA-N

InChI

InChI=1S/C18H20N2O6/c1-5-26-18(22)15-11(3)19-10(2)14(17(21)25-4)16(15)12-7-6-8-13(9-12)20(23)24/h6-9,16,19H,5H2,1-4H3

IUPAC Name

3-ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

SMILES

CCOC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC

Pharmacology

Indication

For the treatment of mild to moderate hypertension

Pharmacodynamics

Nitrendipine, 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. Nitrendipine is similar to other peripheral vasodilators. Nitrendipine 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, Nitrendipine 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.

Target	Actions	Organism
AVoltage-dependent L-type calcium channel subunit alpha-1C	inhibitor	Humans
AVoltage-dependent calcium channel subunit alpha-2/delta-1	inhibitor	Humans
AVoltage-dependent L-type calcium channel subunit beta-2	inhibitor	Humans
AVoltage-dependent calcium channel gamma-1 subunit	inhibitor	Humans
AVoltage-dependent L-type calcium channel subunit alpha-1D	inhibitor	Humans
AVoltage-dependent L-type calcium channel subunit alpha-1S	inhibitor	Humans
UVoltage-dependent calcium channel subunit alpha-2/delta-2	inhibitor	Humans
UVoltage-dependent T-type calcium channel subunit alpha-1H	inhibitor	Humans

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

> 99%

Metabolism

Not Available

Route of elimination

Not Available

Half life

Not Available

Clearance

Not Available

Toxicity

Not Available

Affected organisms

Humans and other mammals

Pathways

Pathway	Category
Nitrendipine Action Pathway	Drug action

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

Drug	Interaction
(R)-warfarin	The serum concentration of (R)-warfarin can be increased when it is combined with Nitrendipine.
(S)-Warfarin	The serum concentration of (S)-Warfarin can be increased when it is combined with Nitrendipine.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid	The therapeutic efficacy of 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid can be increased when used in combination with Nitrendipine.
1-benzylimidazole	1-benzylimidazole may decrease the antihypertensive activities of Nitrendipine.
2,4-thiazolidinedione	The risk or severity of hypoglycemia can be increased when Nitrendipine is combined with 2,4-thiazolidinedione.
2,5-Dimethoxy-4-ethylamphetamine	2,5-Dimethoxy-4-ethylamphetamine may decrease the antihypertensive activities of Nitrendipine.
2,5-Dimethoxy-4-ethylthioamphetamine	2,5-Dimethoxy-4-ethylthioamphetamine may decrease the antihypertensive activities of Nitrendipine.
3,5-diiodothyropropionic acid	The metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Nitrendipine.
4-Bromo-2,5-dimethoxyamphetamine	4-Bromo-2,5-dimethoxyamphetamine may decrease the antihypertensive activities of Nitrendipine.
4-hydroxycoumarin	The metabolism of 4-hydroxycoumarin can be decreased when combined with Nitrendipine.

Food Interactions

Not Available

References

Synthesis Reference

Wolfgang Schmidt, Bernhard Streuff, Manfred Winter, "Preparation of solid medicament formulation containing nitrendipine." U.S. Patent US4724141, issued April, 1980.

US4724141

General References

Not Available

External Links

Human Metabolome Database: HMDB0015187
KEGG Drug: D00629
KEGG Compound: C07713
PubChem Compound: 4507
PubChem Substance: 46508817
ChemSpider: 4351
BindingDB: 50012016
ChEBI: 7582
ChEMBL: CHEMBL475534
Therapeutic Targets Database: DAP001263
PharmGKB: PA146096020
IUPHAR: 2334
Guide to Pharmacology: GtP Drug Page
Wikipedia: Nitrendipine

ATC Codes

C08CA08 — Nitrendipine

C09BB06 — Enalapril and nitrendipine

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Unknown Status	Treatment	High Blood Pressure (Hypertension)	1
4	Withdrawn	Treatment	Chronic Kidney Disease (CKD) / High Blood Pressure (Hypertension)	1

Pharmacoeconomics

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

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	156-160 °C	Not Available
water solubility	Insoluble	Not Available
logP	2.88	MASUMATO,K ET AL. (1995)
Caco2 permeability	-4.77	ADME Research, USCD

Predicted Properties

Property	Value	Source
Water Solubility	0.0142 mg/mL	ALOGPS
logP	3.21	ALOGPS
logP	2.17	ChemAxon
logS	-4.4	ALOGPS
pKa (Strongest Basic)	5.43	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	110.45 Å²	ChemAxon
Rotatable Bond Count	7	ChemAxon
Refractivity	96.91 m³·mol^-1	ChemAxon
Polarizability	36.25 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET features

Property	Value	Probability
Human Intestinal Absorption	+	0.9536
Blood Brain Barrier	-	0.9549
Caco-2 permeable	+	0.7853
P-glycoprotein substrate	Substrate	0.5265
P-glycoprotein inhibitor I	Inhibitor	0.8564
P-glycoprotein inhibitor II	Inhibitor	0.8313
Renal organic cation transporter	Non-inhibitor	0.8984
CYP450 2C9 substrate	Non-substrate	0.8212
CYP450 2D6 substrate	Non-substrate	0.8931
CYP450 3A4 substrate	Substrate	0.7266
CYP450 1A2 substrate	Inhibitor	0.9107
CYP450 2C9 inhibitor	Inhibitor	0.8949
CYP450 2D6 inhibitor	Non-inhibitor	0.9231
CYP450 2C19 inhibitor	Inhibitor	0.8993
CYP450 3A4 inhibitor	Inhibitor	0.8037
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.9247
Ames test	Non AMES toxic	0.7334
Carcinogenicity	Non-carcinogens	0.5186
Biodegradation	Not ready biodegradable	0.9581
Rat acute toxicity	2.3810 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.8131
hERG inhibition (predictor II)	Non-inhibitor	0.9094

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	Not Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	Not Available
LC-MS/MS Spectrum - LC-ESI-QFT , negative	LC-MS/MS	splash10-0ab9-2539000000-3d9a9111a145f234fc24
MS/MS Spectrum - , positive	LC-MS/MS	splash10-016r-0159000000-7b0ccf9fb639868092f0
LC-MS/MS Spectrum - LC-ESI-QFT , positive	LC-MS/MS	splash10-016r-0159000000-4e10a6643ba97ab23a0f

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 / Azacyclic compounds / Enamines
show 6 more
Substituents: Dihydropyridinecarboxylic acid derivative / Nitrobenzene / Nitroaromatic compound / Monocyclic benzene moiety / Dicarboxylic acid or derivatives / Benzenoid / Methyl ester / Enoate ester / Alpha,beta-unsaturated carboxylic ester / Vinylogous amide
show 23 more
Molecular Framework: Aromatic heteromonocyclic compounds
External Descriptors: C-nitro compound, ethyl ester, diester, dihydropyridine (CHEBI:7582)

Targets

Property	Measurement	pH	Temperature (°C)	References
Kd (nM)	0.26	N/A	N/A	2329573
Ki (nM)	0.25	N/A	N/A	2435904

Details1. Voltage-dependent L-type calcium channel subunit alpha-1C

Kind: Protein
Organism: Humans
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

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Striessnig, J. (2004). Ca 2+ channel blockers. In Encyclopedic reference of molecular pharmacology (pp. 201-207). Berlin: Springer. [ISBN:9783540298328]

Details2. Voltage-dependent calcium channel subunit alpha-2/delta-1

Kind: Protein
Organism: Humans
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

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Striessnig, J. (2004). Ca 2+ channel blockers. In Encyclopedic reference of molecular pharmacology (pp. 201-207). Berlin: Springer. [ISBN:9783540298328]

Details3. Voltage-dependent L-type calcium channel subunit beta-2

Kind: Protein
Organism: Humans
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

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Striessnig, J. (2004). Ca 2+ channel blockers. In Encyclopedic reference of molecular pharmacology (pp. 201-207). Berlin: Springer. [ISBN:9783540298328]

Details4. Voltage-dependent calcium channel gamma-1 subunit

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Voltage-gated calcium channel activity
Specific Function: This protein is a subunit of the dihydropyridine (DHP) sensitive calcium channel. Plays a role in excitation-contraction coupling. The skeletal muscle DHP-sensitive Ca(2+) channel may function only...
Gene Name: CACNG1
Uniprot ID: Q06432
Uniprot Name: Voltage-dependent calcium channel gamma-1 subunit
Molecular Weight: 25028.105 Da

References

Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]

Details5. Voltage-dependent L-type calcium channel subunit alpha-1D

Kind: Protein
Organism: Humans
Pharmacological action: Yes
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

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]

Details6. Voltage-dependent L-type calcium channel subunit alpha-1S

Kind: Protein
Organism: Humans
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: CACNA1S
Uniprot ID: Q13698
Uniprot Name: Voltage-dependent L-type calcium channel subunit alpha-1S
Molecular Weight: 212348.1 Da

References

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]

Details7. Voltage-dependent calcium channel subunit alpha-2/delta-2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
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. Acts as a regulatory subunit for P/Q-t...
Gene Name: CACNA2D2
Uniprot ID: Q9NY47
Uniprot Name: Voltage-dependent calcium channel subunit alpha-2/delta-2
Molecular Weight: 129816.095 Da

References

Perez-Reyes E, Van Deusen AL, Vitko I: Molecular pharmacology of human Cav3.2 T-type Ca2+ channels: block by antihypertensives, antiarrhythmics, and their analogs. J Pharmacol Exp Ther. 2009 Feb;328(2):621-7. doi: 10.1124/jpet.108.145672. Epub 2008 Oct 30. [PubMed:18974361]

Details8. Voltage-dependent T-type calcium channel subunit alpha-1H

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Scaffold protein binding
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: CACNA1H
Uniprot ID: O95180
Uniprot Name: Voltage-dependent T-type calcium channel subunit alpha-1H
Molecular Weight: 259160.2 Da

References

Perez-Reyes E, Van Deusen AL, Vitko I: Molecular pharmacology of human Cav3.2 T-type Ca2+ channels: block by antihypertensives, antiarrhythmics, and their analogs. J Pharmacol Exp Ther. 2009 Feb;328(2):621-7. doi: 10.1124/jpet.108.145672. Epub 2008 Oct 30. [PubMed:18974361]

Enzymes

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
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

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]
Klotz U: Interaction potential of lercanidipine, a new vasoselective dihydropyridine calcium antagonist. Arzneimittelforschung. 2002;52(3):155-61. doi: 10.1055/s-0031-1299873. [PubMed:11963641]
Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]

Details2. Cytochrome P450 3A5

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Oxygen binding
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: CYP3A5
Uniprot ID: P20815
Uniprot Name: Cytochrome P450 3A5
Molecular Weight: 57108.065 Da

References

Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]

Details3. Cytochrome P450 3A7

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Oxygen binding
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: CYP3A7
Uniprot ID: P24462
Uniprot Name: Cytochrome P450 3A7
Molecular Weight: 57525.03 Da

References

Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]

Transporters

Details1. Multidrug resistance protein 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Xenobiotic-transporting atpase activity
Specific Function: Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: Multidrug resistance protein 1
Molecular Weight: 141477.255 Da

References

Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS: Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001 Nov;299(2):620-8. [PubMed:11602674]
Takara K, Sakaeda T, Tanigawara Y, Nishiguchi K, Ohmoto N, Horinouchi M, Komada F, Ohnishi N, Yokoyama T, Okumura K: Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression. Eur J Pharm Sci. 2002 Aug;16(3):159-65. [PubMed:12128170]

Details2. Bile salt export pump

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Transporter activity
Specific Function: Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name: ABCB11
Uniprot ID: O95342
Uniprot Name: Bile salt export pump
Molecular Weight: 146405.83 Da

References

Pedersen JM, Matsson P, Bergstrom CA, Hoogstraate J, Noren A, LeCluyse EL, Artursson P: Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43. doi: 10.1093/toxsci/kft197. Epub 2013 Sep 6. [PubMed:24014644]

Drug created on June 13, 2005 07:24 / Updated on March 08, 2019 19:16

Nitrendipine

Identification

Structure for Nitrendipine (DB01054)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

References

References

References

References

References

References

References

Enzymes

References

References

References

Transporters

References

References