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Identification
NameCevimeline
Accession NumberDB00185  (APRD00224)
Typesmall molecule
Groupsapproved
Description

Cevimeline is a parasympathomimetic and muscarinic agonist, with particular effect on M3 receptors. It is indicated by the Food and Drug Administration for the treatment of dry mouth associated with Sjögren’s syndrome. [Wikipedia]

Structure
Thumb
SynonymsNot Available
Salts
Name/CAS Structure Properties
Cevimeline hydrochloride
Thumb
  • InChI Key: WUTYZMFRCNBCHQ-PSASIEDQSA-N
  • Monoisotopic Mass: 199.103084861
  • Average Mass: 199.313
DBSALT000805
Brand names
NameCompany
EvoxacNot Available
SaligrenNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number107233-08-9
WeightAverage: 199.313
Monoisotopic: 199.103084861
Chemical FormulaC10H17NOS
InChI KeyInChIKey=WUTYZMFRCNBCHQ-LHIURRSHSA-N
InChI
InChI=1S/C10H17NOS/c1-8-12-10(7-13-8)6-11-4-2-9(10)3-5-11/h8-9H,2-7H2,1H3/t8?,10-/m1/s1
IUPAC Name
(2R)-5'-methyl-4-azaspiro[bicyclo[2.2.2]octane-2,2'-[1,4]oxathiolane]
SMILES
CC1O[C@@]2(CS1)CN1CCC2CC1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzaspirodecane Derivatives
SubclassNot Available
Direct parentAzaspirodecane Derivatives
Alternative parentsQuinuclidines; Piperidines; Dithioacetals; Oxathiolanes; Tertiary Amines; Polyamines; Ethers; Thioethers
Substituentsquinuclidine; piperidine; oxathiolane; thioacetal; tertiary amine; ether; polyamine; thioether; amine; organonitrogen compound
Classification descriptionThis compound belongs to the azaspirodecane derivatives. These are organic compounds containing a spirodecane moeity with at least one nitrogen atom.
Pharmacology
IndicationFor the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome.
PharmacodynamicsCevimeline is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts.
Mechanism of actionMuscarinic agonists such as cevimeline bind and activate the muscarinic M1 and M3 receptors. The M1 receptors are common in secretory glands (exocrine glands such as salivary and sweat glands), and their activation results in an increase in secretion from the secretory glands. The M3 receptors are found on smooth muscles and in many glands which help to stimulate secretion in salivary glands, and their activation generally results in smooth muscle contraction and increased glandular secretions. Therefore, as saliva excretion is increased, the symptoms of dry mouth are relieved.
AbsorptionRapidly absorbed with peak concentration after 1.5 to 2 hours
Volume of distribution
  • 6 L/kg
Protein binding< 20%
Metabolism

Primarily hepatic, isozymes CYP2D6 and CYP3A4 are responsible for the metabolism of cevimeline. Approximately 44.5% of the drug is converted to cis and trans-sulfoxide, 22.3% to glucuronic acid conjugate, and 4% to N-oxide of cevimeline. Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate.

SubstrateEnzymesProduct
Cevimeline
cevimeline trans-sulfoxideDetails
Cevimeline
cevimeline cis-sulfoxideDetails
Cevimeline
cevimeline cis-sulfoxidationDetails
Cevimeline
cevimeline N-oxideDetails
Cevimeline
    Glucuronic acidDetails
    Route of eliminationAfter 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine.
    Half life5 ± 1 hours
    ClearanceNot Available
    ToxicityNot Available
    Affected organisms
    • Humans and other mammals
    PathwaysNot Available
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.9899
    Blood Brain Barrier + 0.9823
    Caco-2 permeable + 0.6465
    P-glycoprotein substrate Substrate 0.7063
    P-glycoprotein inhibitor I Non-inhibitor 0.6941
    P-glycoprotein inhibitor II Non-inhibitor 0.9434
    Renal organic cation transporter Inhibitor 0.6934
    CYP450 2C9 substrate Non-substrate 0.8083
    CYP450 2D6 substrate Substrate 0.8918
    CYP450 3A4 substrate Substrate 0.5719
    CYP450 1A2 substrate Non-inhibitor 0.8634
    CYP450 2C9 substrate Non-inhibitor 0.9047
    CYP450 2D6 substrate Non-inhibitor 0.6012
    CYP450 2C19 substrate Non-inhibitor 0.7312
    CYP450 3A4 substrate Non-inhibitor 0.9154
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7686
    Ames test Non AMES toxic 0.7969
    Carcinogenicity Non-carcinogens 0.9054
    Biodegradation Not ready biodegradable 0.9942
    Rat acute toxicity 2.7785 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.6383
    hERG inhibition (predictor II) Non-inhibitor 0.8469
    Pharmacoeconomics
    Manufacturers
    • Daiichi sankyo co ltd
    Packagers
    Dosage forms
    FormRouteStrength
    CapsuleOral
    Prices
    Unit descriptionCostUnit
    Evoxac 30 mg capsule2.69USDcapsule
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    United States53408211993-07-072013-07-07
    United States48552901992-08-302009-08-30
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point201-203 °C (HCl salt)Not Available
    water solubilityVery solubleNot Available
    logP1.3Not Available
    Predicted Properties
    PropertyValueSource
    water solubility2.41e+00 g/lALOGPS
    logP1.46ALOGPS
    logP1ChemAxon
    logS-1.9ALOGPS
    pKa (strongest basic)8.59ChemAxon
    physiological charge1ChemAxon
    hydrogen acceptor count2ChemAxon
    hydrogen donor count0ChemAxon
    polar surface area12.47ChemAxon
    rotatable bond count0ChemAxon
    refractivity55.92ChemAxon
    polarizability21.89ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleYesChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis ReferenceNot Available
    General ReferenceNot Available
    External Links
    ResourceLink
    KEGG DrugD00661
    ChEBI3568
    ChEMBL
    Therapeutic Targets DatabaseDAP000075
    PharmGKBPA164754754
    RxListhttp://www.rxlist.com/cgi/generic/cevimeline.htm
    Drugs.comhttp://www.drugs.com/cdi/cevimeline.html
    WikipediaCevimeline
    ATC CodesN07AX03
    AHFS CodesNot Available
    PDB EntriesNot Available
    FDA labelshow(34.3 KB)
    MSDSNot Available
    Interactions
    Drug Interactions
    Drug
    ConivaptanConivaptan may increase the serum concentration of CYP3A4 substrates such as cevimeline. Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates.
    TacrineThe acetylcholinesterase inhibitor, Tacrine, may increase the adverse/toxic effects of Cevimeline, a cholinergic agonist. Monitor for increased cholinergic effects and toxicity.
    Food InteractionsNot Available

    1. Muscarinic acetylcholine receptor M3

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: agonist

    Components

    Name UniProt ID Details
    Muscarinic acetylcholine receptor M3 P20309 Details

    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. Li X, Azlina A, Karabasil MR, Purwanti N, Hasegawa T, Yao C, Akamatsu T, Hosoi K: Degradation of submandibular gland AQP5 by parasympathetic denervation of chorda tympani and its recovery by cevimeline, an M3 muscarinic receptor agonist. Am J Physiol Gastrointest Liver Physiol. 2008 Jul;295(1):G112-G123. Epub 2008 May 1. Pubmed
    4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

    2. Muscarinic acetylcholine receptor M1

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: agonist

    Components

    Name UniProt ID Details
    Muscarinic acetylcholine receptor M1 P11229 Details

    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. Fisher A, Heldman E, Gurwitz D, Haring R, Karton Y, Meshulam H, Pittel Z, Marciano D, Brandeis R, Sadot E, Barg Y, Pinkas-Kramarski R, Vogel Z, Ginzburg I, Treves TA, Verchovsky R, Klimowsky S, Korczyn AD: M1 agonists for the treatment of Alzheimer’s disease. Novel properties and clinical update. Ann N Y Acad Sci. 1996 Jan 17;777:189-96. Pubmed

    1. Cytochrome P450 2D6

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Cytochrome P450 2D6 P10635 Details

    References:

    1. Washio T, Arisawa H, Kohsaka K, Yasuda H: Identification of human drug-metabolizing enzymes involved in the metabolism of SNI-2011. Biol Pharm Bull. 2001 Nov;24(11):1263-6. Pubmed
    2. Washio T, Kohsaka K, Arisawa H, Masunaga H: Pharmacokinetics and metabolism of the novel muscarinic receptor agonist SNI-2011 in rats and dogs. Arzneimittelforschung. 2003;53(1):26-33. Pubmed

    2. Cytochrome P450 3A4

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Cytochrome P450 3A4 P08684 Details

    References:

    1. Washio T, Arisawa H, Kohsaka K, Yasuda H: Identification of human drug-metabolizing enzymes involved in the metabolism of SNI-2011. Biol Pharm Bull. 2001 Nov;24(11):1263-6. Pubmed
    2. Washio T, Kohsaka K, Arisawa H, Masunaga H: Pharmacokinetics and metabolism of the novel muscarinic receptor agonist SNI-2011 in rats and dogs. Arzneimittelforschung. 2003;53(1):26-33. Pubmed

    3. Dimethylaniline monooxygenase [N-oxide-forming] 1

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Dimethylaniline monooxygenase [N-oxide-forming] 1 Q01740 Details

    References:

    1. Washio T, Arisawa H, Kohsaka K, Yasuda H: Identification of human drug-metabolizing enzymes involved in the metabolism of SNI-2011. Biol Pharm Bull. 2001 Nov;24(11):1263-6. Pubmed
    2. Washio T, Kohsaka K, Arisawa H, Masunaga H: Pharmacokinetics and metabolism of the novel muscarinic receptor agonist SNI-2011 in rats and dogs. Arzneimittelforschung. 2003;53(1):26-33. Pubmed

    Comments
    Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:08