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Identification
Name Ciclesonide
Accession Number DB01410
Type small molecule
Groups approved
Description

Ciclesonide is a glucocorticoid used to treat obstructive airway diseases. It is marketed under the brand name Alvesco.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • ciclesonide
Brand names
  • Alvesco
Brand name mixtures Not Available
Categories
  • Anti-Allergic Agents
  • Glucocorticoids
CAS number 141845-82-1
Weight Average: 540.6876
Monoisotopic: 540.308703762
Chemical Formula C32H44O7
InChI Key InChIKey=LUKZNWIVRBCLON-FOMURGDPSA-N
InChI
InChI=1S/C32H44O7/c1-18(2)28(36)37-17-25(35)32-26(38-29(39-32)19-8-6-5-7-9-19)15-23-22-11-10-20-14-21(33)12-13-30(20,3)27(22)24(34)16-31(23,32)4/h12-14,18-19,22-24,26-27,29,34H,5-11,15-17H2,1-4H3/t22-,23-,24-,26+,27+,29?,30-,31-,32+/m0/s1
Plain Text
IUPAC Name
2-[(1S,2S,4R,8S,9S,11S,12S,13R)-6-cyclohexyl-11-hydroxy-9,13-dimethyl-16-oxo-5,7-dioxapentacyclo[10.8.0.0^{2,9}.0^{4,8}.0^{13,18}]icosa-14,17-dien-8-yl]-2-oxoethyl 2-methylpropanoate
SMILES
[H][C@@]12C[C@@]3([H])[C@]4([H])CCC5=CC(=O)C=C[C@]5(C)[C@@]4([H])[C@@H](O)C[C@]3(C)[C@@]1(OC(O2)C1CCCCC1)C(=O)COC(=O)C(C)C
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Steroids and Steroid Derivatives
Substructures
  • Steroids and Steroid Derivatives
  • Carboxylic Acids and Derivatives
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Acetates
  • Acetals and Derivatives
  • Ethers
  • Dioxoles
  • Heterocyclic compounds
  • Alcohols and Polyols
  • Ketones
Pharmacology
Indication For the treatment of nasal symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents 12 years of age and older.
Pharmacodynamics Ciclesonide is a pro-drug that is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following intranasal application. Des-ciclesonide has anti-inflammatory activity with affinity for the glucocorticoid receptor that is 120 times higher than the parent compound. The precise mechanism through which ciclesonide affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic inflammation.
Mechanism of action Glucocorticoids such as ciclesonide can inhibit leukocyte infiltration at the site of inflammation, interfere with mediators of inflammatory response, and suppress humoral immune responses. The antiinflammatory actions of glucocorticoids are thought to involve phospholipase A2 inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes. Ciclesonide reduces inflammatory reaction by limiting the capillary dilatation and permeability of the vascular structures. These compounds restrict the accumulation of polymorphonuclear leukocytes and macrophages and reduce the release of vasoactive kinins. Recent research suggests that corticosteroids may inhibit the release of arachidonic acid from phospholipids, thereby reducing the formation of prostaglandins. Ciclesonide is a glucocorticoid receptor agonist. On binding, the corticoreceptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing an increase or decrease in expression of specific target genes, including suppression of IL2 (interleukin 2) expression.
Absorption Ciclesonide and des-ciclesonide have negligible oral bioavailability (both less than 1%) due to low gastrointestinal absorption and high first-pass metabolism. The intranasal administration of ciclesonide at recommended doses results in negligible serum concentrations of ciclesonide.
Volume of distribution Not Available
Protein binding The percentage of ciclesonide and des-ciclesonide bound to human plasma proteins averaged ≥ 99% each, with ≤ 1% of unbound drug detected in the systemic circulation.
Metabolism

Des-ciclesonide undergoes metabolism in the liver to additional metabolites mainly by the cytochrome P450 (CYP) 3A4 isozyme and to a lesser extent by CYP 2D6.
Route of elimination Not Available
Half life Not Available
Clearance
  • 152 L/hr [Following IV administration of 800 mcg of ciclesonide]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Nycomed us inc
Packagers
Dosage forms
Form Route Strength
Aerosol, metered Nasal
Aerosol, metered Respiratory (inhalation)
Prices
Unit description Cost Unit
Alvesco 160 mcg/act Aerosol 6.1 gm Inhaler 162.24 USD inhaler
Alvesco 80 mcg/act Aerosol 6.1 gm Inhaler 162.24 USD inhaler
Alvesco 160 mcg inhaler 31.1 USD g
Alvesco 80 mcg inhaler 31.1 USD g
Omnaris 50 mcg nasal spray 11.01 USD g
Alvesco 200 mcg/dose Metered Dose Aerosol 0.66 USD dose
Alvesco 100 mcg/dose Metered Dose Aerosol 0.4 USD dose
Patents
Country Patent Number Approved Expires
United States 6767901 2000-10-21 2020-10-21
United States 5695743 1993-07-06 2010-07-06
Canada 2388325 2007-09-18 2020-10-20
Canada 2050812 2003-07-29 2011-09-06
Properties
State solid
Melting point Not Available
Experimental Properties Not Available
Predicted Properties
Property Value Source
water solubility 1.57e-03 g/l ALOGPS
logP 4.08 ALOGPS
logP 5.32 ChemAxon Molconvert
logS -5.54 ALOGPS
pKa 15.56 ChemAxon Molconvert
hydrogen acceptor count 6 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 99.13 ChemAxon Molconvert
rotatable bond count 6 ChemAxon Molconvert
refractivity 146.28 ChemAxon Molconvert
polarizability 60.21 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Mutch E, Nave R, McCracken N, Zech K, Williams FM: The role of esterases in the metabolism of ciclesonide to desisobutyryl-ciclesonide in human tissue. Biochem Pharmacol. 2007 May 15;73(10):1657-64. Epub 2007 Jan 28. Pubmed
External Links
Resource Link
KEGG Drug D01703 Link_out
PubChem Compound 444033 Link_out
PubChem Substance 46508553 Link_out
ChemSpider 392056 Link_out
Therapeutic Targets Database DAP000423 Link_out
Drug Product Database 2285606 Link_out
RxList http://www.rxlist.com/cgi/generic/omnaris.htm Link_out
Drugs.com http://www.drugs.com/cdi/ciclesonide-spray.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Ciclesonide Link_out
ATC Codes
  • R03BA08
AHFS Codes
  • 68:04.00
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Glucocorticoid receptor

Pharmacological action: yes
Actions: agonist

Receptor for glucocorticoids (GC). Has a dual mode of action:as a transcription factor that binds to glucocorticoid response elements (GRE) and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth

Organism class: human
UniProt ID: P04150 Link_out
Gene: NR3C1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Barnes NC: The properties of inhaled corticosteroids: similarities and differences. Prim Care Respir J. 2007 Jun;16(3):149-54. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2D6

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Peet CF, Enos T, Nave R, Zech K, Hall M: Identification of enzymes involved in phase I metabolism of ciclesonide by human liver microsomes. Eur J Drug Metab Pharmacokinet. 2005 Oct-Dec;30(4):275-86. Pubmed

3. Liver carboxylesterase 1

Actions: substrate

Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl CoA ester

UniProt ID: P23141 Link_out
Gene: CES1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Mutch E, Nave R, McCracken N, Zech K, Williams FM: The role of esterases in the metabolism of ciclesonide to desisobutyryl-ciclesonide in human tissue. Biochem Pharmacol. 2007 May 15;73(10):1657-64. Epub 2007 Jan 28. Pubmed
Carriers

1. Corticosteroid-binding globulin

Actions: binder

Major transport protein for glucocorticoids and progestins in the blood of almost all vertebrate species

UniProt ID: P08185 Link_out
Gene: SERPINA6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. 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
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Comments
Drug created on July 17, 2007 06:38 / Updated on October 05, 2011 15:20

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.