Moxonidine
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
Structure for Moxonidine (DB09242)
- 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
- 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].
Target Actions Organism AAlpha-2A adrenergic receptor agonistHuman ANischarin agonistHuman - 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
Drug Interaction 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Moxonidine. Acebutolol The therapeutic efficacy of Moxonidine can be decreased when used in combination with Acebutolol. Acemetacin The therapeutic efficacy of Moxonidine can be decreased when used in combination with Acemetacin. Acepromazine Acepromazine may decrease the vasoconstricting activities of Moxonidine. Acetylsalicylic acid The therapeutic efficacy of Moxonidine can be decreased when used in combination with Acetylsalicylic acid. Aldesleukin The risk or severity of adverse effects can be increased when Moxonidine is combined with Aldesleukin. Alfuzosin Alfuzosin may increase the hypotensive activities of Moxonidine. Aliskiren Moxonidine may increase the hypotensive activities of Aliskiren. Alprenolol Moxonidine may increase the atrioventricular blocking (AV block) activities of Alprenolol. Ambrisentan Moxonidine may increase the hypotensive activities of Ambrisentan. - Food Interactions
- Not Available
References
- General References
- 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]
- Fenton C, Keating GM, Lyseng-Williamson KA: Moxonidine: a review of its use in essential hypertension. Drugs. 2006;66(4):477-96. [PubMed:16597164]
- 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]
- 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]
- 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]
- 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]
- 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 diuretics
- C02LC — Imidazoline receptor agonists in combination with diuretics
- C02L — ANTIHYPERTENSIVES AND DIURETICS IN COMBINATION
- C02 — ANTIHYPERTENSIVES
- C — CARDIOVASCULAR SYSTEM
- FDA label
- Download (108 KB)
- MSDS
- Download (56.5 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment High Blood Pressure (Hypertension) 1 3 Terminated Prevention Cardiac Diseases / Vascular Surgery 1 4 Completed Treatment High Blood Pressure (Hypertension) / Metabolic Syndromes / Obesity, Abdominal 1 4 Completed Treatment Nonvalvular Atrial Fibrillation 1 4 Completed Treatment Polycystic Ovaries Syndrome 1 4 Unknown Status Not Available BMI >27 kg/m2 / BMI >30 kg/m2 1 4 Unknown Status Treatment Diabetic Nephropathies 1 4 Unknown Status Treatment High Blood Pressure (Hypertension) / Obesity, Abdominal 1 4 Unknown Status Treatment Schizophrenic Disorders 1 Not Available Completed Basic Science Arterial Hypertension / Osteopenia 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) 197 – 205 MSDS water solubility <1 mg/mL MSDS - Predicted Properties
Property Value Source Water Solubility 0.114 mg/mL ALOGPS logP 1.01 ALOGPS logP 1.54 ChemAxon logS -3.3 ALOGPS pKa (Strongest Basic) 7.26 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 6 ChemAxon Hydrogen Donor Count 2 ChemAxon Polar Surface Area 71.43 Å2 ChemAxon Rotatable Bond Count 2 ChemAxon Refractivity 63.41 m3·mol-1 ChemAxon Polarizability 23.57 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
- Not Available
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
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
- 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]
- 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]
- 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
- 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]
- 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 August 02, 2018 06:16