This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Name
Moxonidine
Accession Number
DB09242
Type
Small Molecule
Groups
Approved, Investigational
Description

Moxonidine is a new-generation centrally acting antihypertensive drug approved for the treatment of mild to moderate essential hypertension. It may have a role when thiazides, beta-blockers, ACE inhibitors and calcium channel blockers are not appropriate or have failed to control blood pressure. In addition, it demonstrates favourable effects on parameters of the insulin resistance syndrome, apparently independent of blood pressure reduction.

Structure
Thumb
Synonyms
  • (2R,4R)-1-[(2S)-5-[(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8- quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid
  • Moxonidina
External IDs
BDF-5896 / BDF5896 / BE5895 / LY-326869 / LY326869
International/Other Brands
Cynt / Physiotens (Solvay Pharmaceuticals)
Categories
UNII
CC6X0L40GW
CAS number
75438-57-2
Weight
Average: 241.677
Monoisotopic: 241.073037738
Chemical Formula
C9H12ClN5O
InChI Key
WPNJAUFVNXKLIM-UHFFFAOYSA-N
InChI
InChI=1S/C9H12ClN5O/c1-5-13-7(10)6(8(14-5)16-2)15-9-11-3-4-12-9/h3-4H2,1-2H3,(H2,11,12,15)
IUPAC Name
4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methylpyrimidin-5-amine
SMILES
COC1=NC(C)=NC(Cl)=C1NC1=NCCN1

Pharmacology

Indication

For the treatment of mild to moderate essential or primary hypertension [7]. Effective as most first-line antihypertensives when used as monotherapy [2].

Pharmacodynamics

Antihypertensive agent whose site of action is the Central Nervous System (CNS), specifically involving interactions with I1- imidazoline and alpha-2-adrenergic rececptors within the rostral ventrolateral medulla (RSV). [Label]

Mechanism of action

Stimulation of central alpha 2-adrenergic receptors is associated with sympathoadrenal suppression and subsequent reduction of blood pressure. As this class was further explored it was discovered that sympathoadrenal activity can also be suppressed by a second pathway with a newly discovered drug target specific to imidazolines [5]. Specifically, moxonidine binds the imidazoline receptor subtype 1 (I1) and to a lesser extent αlpha-2-adrenoreceptors in the RSV causing a reduction of sympathetic activity, reducing systemic vascular resistance and thus arterial blood pressure. [Label]

Moreover, since alpha-2-adrenergic receptors are considered the primary molecular target that facilitates the most common side effects of sedation and dry mouth that are elicited by most centrally acting antihypertensives, moxonidine differs from these other centrally acting antihypertensives by demonstrating only low affinity for central alpha-2-adrenoceptors compared to the aforementioned I1-imidazoline receptors [Label].

TargetActionsOrganism
AAlpha-2A adrenergic receptor
agonist
Human
ANischarin
agonist
Human
Absorption

90% of an oral dose is absorbed with negligible interference from food intake or first pass metabolism, resulting in a high bioavailability of 88%. [Label]

Volume of distribution

1.8±0.4L/kg. [Label]

Protein binding

About 10% of moxonidine is bound to plasma proteins. [Label]

Metabolism

Biotransformation is unimportant [3] with 10-20% of moxonidine undergoing oxidation reactions to the primary 4,5-dehydromoxonidine metabolite and a guanidine derivative by opening of the imidazoline ring. [Label]

The antihypertensive effects of these 4,5-dehydromoxonidine and guanidine metabolites are only 1/10 and 1/100 the effect of moxonidine [Label].

Oxidation on either the methyl group (pyrimidine ring) or on the imidazole ring of moxonidine results in the formation of the hydroxylmethyl moxonidine metabolite or the hydroxy moxonidine metabolite [6]. The hydroxy moxonidine metabolite can be further oxidized to the dihydroxy metabolite or it can lose water to form the dehydrogenated moxonidine metabolite, which itself can be further oxidized to form an N-oxide [6]. Aside from these Phase I metabolites, Phase II metabolism of moxonidine is also evident with the presence of a cysteine conjugate metabolite minus chlorine [6]. Nevertheless, the identification of the hydroxy moxonidine metabolite with a high level of dehydrogenated moxonidine metabolite in human urine samples suggests that dehydrogenation from the hydroxy metabolite to the dehydrogenated moxonidine metabolite represents the primary metabolic pathway in humans [6].

The cytochromes P450 responsible for the metabolism of moxonidine in humans have not yet been determined [6].

Ultimately, the parent moxonidine compound was observed to be the most abundant component in different biological matrices of urinary excretion samples, verifying that metabolism only plays a modest role in the clearance of moxonidine in humans [6].

Route of elimination

Elimination is nearly entirely via the kidneys with a majority (50 -75%) of overall moxonidine being eliminated unchanged through renal excretion. Ultimately, more than 90% of a dose is eliminated by way of the kidneys within the first 24 hours after administration, with only approximately 1% being eliminiated via faeces. [Label]

Half life

Plasma elimination half life is 2.2 - 2.3 hours while renal elimination half life is 2.6-2.8 hours. [Label]

Clearance

Administered twice daily due to short half life [Label].

However, lower dosage adjustments and close monitoring is necessary in elderly and renal impairment patients due to reduced clearance. In particular, the exposure AUC can increase by about 50% following a single dose and at steady state in elderly patients and moderately impaired renal function with GFR between 30-60 mL/min can cause AUC increases by 85% and decreases in clearence to 52 %. [Label]

Toxicity
  • Contraindicated due to known hypersensitivity to an ingredient (Physiotens tablets contain lactose), heart failure, severe renal impairment, < 16 years old, >75 years old, bradycardia, severe bradyarrhythmia, sick sinus syndrome, second or third degree atrioventricular block, malignant arrhythmias. [Label]
  • Used with caution in patients with history of severe coronary artery disease (CAD), unstable angina, angioneurotic edema. [Label]
  • Pregnancy Category B3:Avoid use during pregnancy (inadequate data in pregnant woman) and lactation (maternal blood stream transfer to breast milk shown) unless benefit clearly justifies risk. [Label]
  • Lack of specific therapeutic experience in cases of intermittent claudication, Raynaud's disease, Parkinson's disease, epileptic disorders, gluacoma, and depression suggest moxonidine should not be used in such instances [Label].
  • Carcinogenicity and genotoxicity does not appear significant. [Label]
  • Concurrent administration of other hypotensives or sedative and hypnotics can enhance the hypotensive effect and intensify sedation respectively. [Label]
  • Avoid concurrent Tricyclic Antidepressant (TCA) use to avoid reduction of monoxidine efficacy. [Label]
  • Generally well tolerated with dry mouth and headache the most common adverse effects [Label]
  • Symptoms of overdose correlate with pharmacodynamic properties:hypotension, sedation, orthostatic dysregulation, bradycardia, dry mouth with no specific counter-treatment known. [Label]
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcebutololThe therapeutic efficacy of Moxonidine can be decreased when used in combination with Acebutolol.
AceclofenacThe therapeutic efficacy of Moxonidine can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Moxonidine can be decreased when used in combination with Acemetacin.
AcepromazineThe therapeutic efficacy of Moxonidine can be decreased when used in combination with Acepromazine.
Acetylsalicylic acidThe therapeutic efficacy of Moxonidine can be decreased when used in combination with Acetylsalicylic acid.
AlclofenacThe therapeutic efficacy of Moxonidine can be decreased when used in combination with Alclofenac.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Moxonidine.
AlfuzosinAlfuzosin may increase the hypotensive activities of Moxonidine.
AliskirenThe risk or severity of adverse effects can be increased when Aliskiren is combined with Moxonidine.
AlminoprofenThe therapeutic efficacy of Moxonidine can be decreased when used in combination with Alminoprofen.
Food Interactions
Not Available

References

General References
  1. Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, Wiltse C, Wright TJ: Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail. 2003 Oct;5(5):659-67. [PubMed:14607206]
  2. Fenton C, Keating GM, Lyseng-Williamson KA: Moxonidine: a review of its use in essential hypertension. Drugs. 2006;66(4):477-96. [PubMed:16597164]
  3. Prichard BN, Owens CW, Graham BR: Pharmacology and clinical use of moxonidine, a new centrally acting sympatholytic antihypertensive agent. J Hum Hypertens. 1997 Aug;11 Suppl 1:S29-45. [PubMed:9321737]
  4. Prichard BN, Graham BR: I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors: implications for the treatment of the elderly. Drugs Aging. 2000 Aug;17(2):133-59. [PubMed:10984201]
  5. Ernsberger P, Haxhiu MA, Graff LM, Collins LA, Dreshaj I, Grove DL, Graves ME, Schafer SG, Christen MO: A novel mechanism of action for hypertension control: moxonidine as a selective I1-imidazoline agonist. Cardiovasc Drugs Ther. 1994 Mar;8 Suppl 1:27-41. [PubMed:8068578]
  6. He MM, Abraham TL, Lindsay TJ, Schaefer HC, Pouliquen IJ, Payne C, Czeskis B, Shipley LA, Oliver SD, Mitchell MI: Metabolism and disposition of the antihypertensive agent moxonidine in humans. Drug Metab Dispos. 2003 Mar;31(3):334-42. [PubMed:12584161]
  7. Electronic Medicines Compedium Physiotens (Moxonidine) Monograph [Link]
External Links
Human Metabolome Database
HMDB0041938
KEGG Drug
D05087
KEGG Compound
C07451
PubChem Compound
4810
PubChem Substance
310265145
ChemSpider
4645
BindingDB
50050093
ChEBI
7009
ChEMBL
CHEMBL19236
Wikipedia
Moxonidine
ATC Codes
C02LC05 — Moxonidine and diureticsC02AC05 — Moxonidine
FDA label
Download (108 KB)
MSDS
Download (56.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentHigh Blood Pressure (Hypertension)1
3TerminatedPreventionCardiac Diseases / Vascular Surgery1
4CompletedTreatmentHigh Blood Pressure (Hypertension) / Metabolic Syndromes / Obesity, Abdominal1
4CompletedTreatmentNonvalvular Atrial Fibrillation1
4CompletedTreatmentPolycystic Ovaries Syndrome1
4Unknown StatusNot AvailableBMI >27 kg/m2 / BMI >30 kg/m21
4Unknown StatusTreatmentDiabetic Nephropathies1
4Unknown StatusTreatmentHigh Blood Pressure (Hypertension) / Obesity, Abdominal1
4Unknown StatusTreatmentSchizophrenic Disorders1
Not AvailableCompletedBasic ScienceArterial Hypertension / Osteopenia1

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)197 – 205MSDS
water solubility<1 mg/mLMSDS
Predicted Properties
PropertyValueSource
Water Solubility0.114 mg/mLALOGPS
logP1.01ALOGPS
logP1.54ChemAxon
logS-3.3ALOGPS
pKa (Strongest Basic)7.26ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area71.43 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity63.41 m3·mol-1ChemAxon
Polarizability23.57 Å3ChemAxon
Number of Rings2ChemAxon
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 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

Taxonomy

Description
This compound belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazines
Sub Class
Pyrimidines and pyrimidine derivatives
Direct Parent
Halopyrimidines
Alternative Parents
Aminopyrimidines and derivatives / Alkyl aryl ethers / Aryl chlorides / Imidazolines / Heteroaromatic compounds / Guanidines / Propargyl-type 1,3-dipolar organic compounds / Carboximidamides / Azacyclic compounds / Organopnictogen compounds
show 2 more
Substituents
Alkyl aryl ether / Aminopyrimidine / Halopyrimidine / Aryl chloride / Aryl halide / Heteroaromatic compound / 2-imidazoline / Guanidine / Ether / Azacycle
show 12 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyrimidines, organohalogen compound (CHEBI:7009)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...
Gene Name
ADRA2A
Uniprot ID
P08913
Uniprot Name
Alpha-2A adrenergic receptor
Molecular Weight
48956.275 Da
References
  1. Zhu QM, Lesnick JD, Jasper JR, MacLennan SJ, Dillon MP, Eglen RM, Blue DR Jr: Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor transgenic mice. Br J Pharmacol. 1999 Mar;126(6):1522-30. [PubMed:10217548]
  2. Stone LS, Fairbanks CA, Wilcox GL: Moxonidine, a mixed alpha(2)-adrenergic and imidazoline receptor agonist, identifies a novel adrenergic target for spinal analgesia. Ann N Y Acad Sci. 2003 Dec;1009:378-85. [PubMed:15028616]
  3. Buccafusco JJ, Lapp CA, Westbrooks KL, Ernsberger P: Role of medullary I1-imidazoline and alpha 2-adrenergic receptors in the antihypertensive responses evoked by central administration of clonidine analogs in conscious spontaneously hypertensive rats. J Pharmacol Exp Ther. 1995 Jun;273(3):1162-71. [PubMed:7791087]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Phosphatidylinositol binding
Specific Function
Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling. Binds numerous imidazoline ligands that induces initiation of cell-si...
Gene Name
NISCH
Uniprot ID
Q9Y2I1
Uniprot Name
Nischarin
Molecular Weight
166627.105 Da
References
  1. Ernsberger P, Damon TH, Graff LM, Schafer SG, Christen MO: Moxonidine, a centrally acting antihypertensive agent, is a selective ligand for I1-imidazoline sites. J Pharmacol Exp Ther. 1993 Jan;264(1):172-82. [PubMed:8380858]
  2. Buccafusco JJ, Lapp CA, Westbrooks KL, Ernsberger P: Role of medullary I1-imidazoline and alpha 2-adrenergic receptors in the antihypertensive responses evoked by central administration of clonidine analogs in conscious spontaneously hypertensive rats. J Pharmacol Exp Ther. 1995 Jun;273(3):1162-71. [PubMed:7791087]

Drug created on October 23, 2015 14:26 / Updated on November 05, 2018 17:49