Identification

Name
Nicorandil
Accession Number
DB09220
Type
Small Molecule
Groups
Approved, Investigational
Description

Nicorandil is an orally efficacious vasodilatory drug and antianginal agent marketed in the UK, Australia, most of Europe, India, Philippines, Japan, South Korea, and Taiwan. It is not an approved drug by FDA. It is a niacinamide derivative that induces vasodilation of arterioles and large coronary arteries by activating potassium channels. It is often used for patients with angina who remain symptomatic despite optimal treatment ith other antianginal drugs [11]. Nicorandil is a dual-action potassium channel opener that relaxes vascular smooth muscle through membrane hyperpolarization via increased transmembrane potassium conductance and increased intracellular concentration of cyclic GMP. It is shown to dilate normal and stenotic coronary arteries and reduces both ventricular preload and afterload [10].

Structure
Thumb
Synonyms
  • 2-Nicotinamidoethyl nitrate
  • N-(2-Hydroxyethyl)nicotinamide nitrate
  • N-(2-Hydroxyethyl)nicotinamide nitrate (ester)
  • Nicorandilum
External IDs
BRN 0481451 / SG-75
International/Other Brands
Adancor (Merck) / Angedil (Egis Pharmaceuticals) / Angicor (Sanofi-Aventis) / Aprior (OEP Phils) / Av-Cor (Strides Arcolab) / Corangi (Unimed & Unihealth) / Cordinik (PIQ-Farma) / Corflo (Wockhardt) / Dancor (Merck) / Ikorel (Sanofi) / Ikotril (Sanofi-aventis) / K-Cor (Macleods) / Nicodil (Genovate) / Nicoduce (AHPL) / Nicolan (G.L. Pharma) / Nicoline (Johnlee) / Nicor (Orion) / Nicoral (General Pharma) / Nicostar (Lupin) / Nidil (Shou Chan) / Nikoran (Torrent) / Nikoranmart (Towa Yakuhin) / Nirandil (Standard) / Randil (Adwia) / Sigmart (Chugai) / Silvinol (Nisshin Pharmaceutical) / Zynicor (Zydus)
Categories
UNII
260456HAM0
CAS number
65141-46-0
Weight
Average: 211.177
Monoisotopic: 211.059305782
Chemical Formula
C8H9N3O4
InChI Key
LBHIOVVIQHSOQN-UHFFFAOYSA-N
InChI
InChI=1S/C8H9N3O4/c12-8(7-2-1-3-9-6-7)10-4-5-15-11(13)14/h1-3,6H,4-5H2,(H,10,12)
IUPAC Name
2-[(pyridin-3-yl)formamido]ethyl nitrate
SMILES
[O-][N+](=O)OCCNC(=O)C1=CC=CN=C1

Pharmacology

Indication

Indicated for the prevention and treatment of chronic stable angina pectoris and reduction in the risk of acute coronary syndromes.

Pharmacodynamics

Nicorandil is a potassium channel opener with nitrovasodilator (NO donor) actions, making it both an arterial and a venous dilator [11]. It causes sustained dilation of both the arterial resistance and conductive vessels that increases coronary blood flow, however the effect of the drug on coronary arteries does not involve the coronary steal phenomenon [12]. Activation of potassium channels lead to hyperpolarization of the smooth muscle cells, followed by arterial dilation and afterload reduction. Nicorandil is shown to increase pooling in the capacitance vessels with a decrease in preload through relaxing the venous vascular system. Overall, improved blood flow and reduced infarct size are achieved through reduction of end-diastolix pressure and decreased extravascular component of vascular resistance [12]. Open studies showed the effectiveness of nicorandil treatment on various types of angina pectoris [8].

Mechanism of action

Nicorandil mediates its therapeutic efficacy via two main mechanisms. Nicorandil is an activator and opener of ATP-sensitive (ATP-dependent) potassium channels (KATP channels) that are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) subunits. Nicorandil binding sites are located in the sulfonylurea receptor 2 (SUR2) in the ATP-sensitive potassium channel [4], which are regulatory subunits of the channel that exhibit an ATPase activitiy [2]. There are 2 types of SUR2 subunits (2A/2B) that have identical nucleotide binding domains (NBD), where SUR2A is more predominantly expressed in skeletal and cardiac myocytes and SUR2B in smooth muscle cells [2]. Nicorandil more potently activates SUR2B/Kir6.2 than SUR2A/Kir6.2 channels to cause hyperpolarization. ATP-NBD1 interaction influences the channel signalling by nicorandil, and the response of the channel to nicorandil is also facilitated and heightened by the interaction of ATP or ADP with NBD2 [3]. Potentiated activity of ATP-sensitive channels have cardioprotective role by limiting the duration of action potentials and preventing intraceullar calcium overload [7]. This attenuates cellular injury by preserving cellular energetics and ultimately cell survival [6]. KATP channel-dependent membrane hyperpolarization can also lead to vasodilation via reduction in Ca2+ influx through the voltage-gated Ca2+ channels and regulation of intracellular Ca2+ mobilization in smooth muscle cells [6]. Nicorandil contain a nitrate moiety in its structure, making it a good dilator of vascular smooth muscle like other nitroglycerin esters [5]. Direct relaxation of venous vascular system arises from NO-donor mediated stimulation of guanylyl cyclase and increased levels of intracellular cyclic GMP (cGMP). Elevated levels of cGMP contributes to the total relaxing effect of nicorandil at higher concentrations of the drug [1].

TargetActionsOrganism
AATP-binding cassette sub-family C member 9
activator
Human
Absorption

Following oral administration, nicorandil is well absorbed from the gastrointestinal tract with the oral bioavailability of 75% with the maximum peak plasma concentration (Cmax) reached within 30-60 minutes. The mean Cmax is Cmax then is approximately 300 ng/ml [9]. Steady-state plasma concentrations of nicorandil usually are reached within approximately 96-120 h after twice daily dosing (10 or 20mg) [12].

Volume of distribution

After oral (and i.v.) administration of the drug, the apparent volume of distribution is approximately 1.0-1.4 L/kg body weight [9].

Protein binding

Nicorandil is about 25% bound to human albumin and other plasma proteins [9].

Metabolism

Nicorandil undergoes extensive hepatic metabolism [12]. The main biotransformation pathways of nicorandil are denitration, followed by subsequent nicotinamide metabolism. The main pharmacologically inactive denitrated metabolite 2-nicotinamidoethanol can be detected in the urine. The derivatives formed from the nicotinamide metabolism of denitrated products are nicotinuric acid, nicotinamide, N-methylnicotinamide and nicotinic acid [12].

Route of elimination

The main route of elimination is the kidney with more than 60% of the administered dose was eliminated in the urine 24 hours after dosing [12]. Only approximately 1% of nicorandil is excreted unchanged in the urine, and the remaining compounds are mainly the denitrated metabolite (9%) and its derivatives (e.g. nicotinuric acid 6%, nicotinamide 1%, N-methylnicotinamide < 1% and nicotinic acid < 1%) [12]. Less than 2% of administered dose is excreted through the biliary system [9].

Half life

The elimination half life is approximately 1 hour [9].

Clearance

The total body clearance is approximately 1.15 L/min [9].

Toxicity

Common adverse effects include lethargy, back pain, chest pain, infection, feeling of weakness. In the cardiovascular system, hypotension, increased heart rate in higher doses, palpitations, worsened angina pectoris and vasodilation/flush may be observed. Dyspepsia, nausea, and vomiting may occur as gastrointestinal disorders. Headaches may arise from vasodilation. Other common side effects include myalgia, bronchitis, dyspnoea, and respiratory disorder [12]. Nicorandil does not affect fertility of male or female rats, and shows no potential in carcinogenic, mutagenic or genotoxic studies [12]. Oral LD50 values in mouse, rat and dog are 626 mg/kg, 1220 mg/kg and 62.5 mg/kg, respectively [MSDS].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
16-BromoepiandrosteroneThe risk or severity of adverse effects can be increased when 16-Bromoepiandrosterone is combined with Nicorandil.
19-norandrostenedioneThe risk or severity of adverse effects can be increased when 19-norandrostenedione is combined with Nicorandil.
5-androstenedioneThe risk or severity of adverse effects can be increased when 5-androstenedione is combined with Nicorandil.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Nicorandil.
AcebutololNicorandil may increase the hypotensive activities of Acebutolol.
AcemetacinThe therapeutic efficacy of Nicorandil can be decreased when used in combination with Acemetacin.
AcetaminophenAcetaminophen may decrease the excretion rate of Nicorandil which could result in a higher serum level.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Nicorandil.
AlclometasoneThe risk or severity of ulceration can be increased when Alclometasone is combined with Nicorandil.
AldesleukinNicorandil may increase the hypotensive activities of Aldesleukin.
Food Interactions
Not Available

References

General References
  1. Kukovetz WR, Holzmann S, Poch G: Molecular mechanism of action of nicorandil. J Cardiovasc Pharmacol. 1992;20 Suppl 3:S1-7. [PubMed:1282168]
  2. Russ U, Lange U, Loffler-Walz C, Hambrock A, Quast U: Binding and effect of K ATP channel openers in the absence of Mg2+. Br J Pharmacol. 2003 May;139(2):368-80. [PubMed:12770942]
  3. Yamada M, Kurachi Y: The nucleotide-binding domains of sulfonylurea receptor 2A and 2B play different functional roles in nicorandil-induced activation of ATP-sensitive K+ channels. Mol Pharmacol. 2004 May;65(5):1198-207. [PubMed:15102948]
  4. Tamura Y, Tanabe K, Kitagawa W, Uchida S, Schreiner GF, Johnson RJ, Nakagawa T: Nicorandil, a K(atp) channel opener, alleviates chronic renal injury by targeting podocytes and macrophages. Am J Physiol Renal Physiol. 2012 Aug 1;303(3):F339-49. doi: 10.1152/ajprenal.00158.2012. Epub 2012 May 23. [PubMed:22622455]
  5. Fujiwara T, Angus JA: Analysis of relaxation and repolarization mechanisms of nicorandil in rat mesenteric artery. Br J Pharmacol. 1996 Dec;119(8):1549-56. [PubMed:8982500]
  6. Jahangir A, Terzic A: K(ATP) channel therapeutics at the bedside. J Mol Cell Cardiol. 2005 Jul;39(1):99-112. [PubMed:15953614]
  7. Kane GC, Liu XK, Yamada S, Olson TM, Terzic A: Cardiac KATP channels in health and disease. J Mol Cell Cardiol. 2005 Jun;38(6):937-43. Epub 2005 Apr 25. [PubMed:15910878]
  8. Frampton J, Buckley MM, Fitton A: Nicorandil. A review of its pharmacology and therapeutic efficacy in angina pectoris. Drugs. 1992 Oct;44(4):625-55. [PubMed:1281076]
  9. Frydman A: Pharmacokinetic profile of nicorandil in humans: an overview. J Cardiovasc Pharmacol. 1992;20 Suppl 3:S34-44. [PubMed:1282174]
  10. Goldschmidt M, Landzberg BR, Frishman WH: Nicorandil: a potassium channel opening drug for treatment of ischemic heart disease. J Clin Pharmacol. 1996 Jul;36(7):559-72. [PubMed:8844437]
  11. 21. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 261). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
  12. IKOREL (Nicorandil) Product Information [Link]
  13. UK Medicines and Healthcare products Regulatory Agency (MHRA): Nicorandil Tablets_Scientific Discussion [Link]
External Links
KEGG Drug
D01810
KEGG Compound
C13280
PubChem Compound
47528
PubChem Substance
310265127
ChemSpider
43240
ChEBI
31905
ChEMBL
CHEMBL284906
Wikipedia
Nicorandil
ATC Codes
C01DX16 — Nicorandil
MSDS
Download (202 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Enrolling by InvitationPreventionRadiation Pneumonitis1
3RecruitingTreatmentMyocardial Infarction1
4Active Not RecruitingPreventionCoronary Artery Disease / End Stage Renal Disease (ESRD)1
4CompletedTreatmentCoronary Heart Disease (CHD) / Stable Angina (SA)1
4CompletedTreatmentNormal, or Near Normal Coronary Angiography / Slow Coronary Flow / Stable Angina (SA)1
4Enrolling by InvitationTreatmentMyocardial Infarction / Nicorandil / Percutaneous Coronary Intervention1
4Not Yet RecruitingTreatmentST Segment Elevation Myocardial Infarction (STEMI)1
4RecruitingPreventionCoronary Heart Disease (CHD)1
4RecruitingTreatmentNon-obstructive Coronary Artery Disease1
4Unknown StatusTreatmentChronic Stable Angina Pectoris1
4Unknown StatusTreatmentDiabetes Mellitus (DM) / Unstable Angina (UA)1
4WithdrawnTreatmentAngina Pectoris1
Not AvailableCompletedPreventionAcute Myocardial Infarction (AMI) / Congestive Heart Failure (CHF)1
Not AvailableCompletedTreatmentAcute Myocardial Infarction (AMI)1
Not AvailableTerminatedTreatmentHigh Blood Pressure (Hypertension) / Microvascular Angina1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)92-93MSDS
water solubilityPartly miscibleMSDS
Predicted Properties
PropertyValueSource
Water Solubility1.19 mg/mLALOGPS
logP0ALOGPS
logP-0.16ChemAxon
logS-2.2ALOGPS
pKa (Strongest Acidic)13.81ChemAxon
pKa (Strongest Basic)3.62ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area94.36 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity49.86 m3·mol-1ChemAxon
Polarizability19.34 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-0900000000-9439cd529fafd85e86db

Taxonomy

Description
This compound belongs to the class of organic compounds known as nicotinamides. These are heterocyclic aromatic compounds containing a pyridine ring substituted at position 3 by a carboxamide group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Pyridinecarboxylic acids and derivatives
Direct Parent
Nicotinamides
Alternative Parents
Heteroaromatic compounds / Alkyl nitrates / Secondary carboxylic acid amides / Organic nitro compounds / Organic nitric acids and derivatives / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organic zwitterions
show 2 more
Substituents
Nicotinamide / Organic nitrate / Alkyl nitrate / Heteroaromatic compound / Carboxamide group / Organic nitric acid or derivatives / Secondary carboxylic acid amide / Organic nitro compound / Organic 1,3-dipolar compound / Allyl-type 1,3-dipolar organic compound
show 11 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyridinecarboxamide, nitrate ester (CHEBI:31905)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Activator
General Function
Transporter activity
Specific Function
Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with KCNJ11. KCNJ11 forms the channel pore while ABCC9 is required for activation and regul...
Gene Name
ABCC9
Uniprot ID
O60706
Uniprot Name
ATP-binding cassette sub-family C member 9
Molecular Weight
174221.7 Da
References
  1. Russ U, Lange U, Loffler-Walz C, Hambrock A, Quast U: Binding and effect of K ATP channel openers in the absence of Mg2+. Br J Pharmacol. 2003 May;139(2):368-80. [PubMed:12770942]

Drug created on October 21, 2015 18:43 / Updated on August 02, 2018 06:15