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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
Synonyms
2-Methyspiro(1,3-oxathiolane-5,3)quinuclidine
Cevimelina
Cevimelinum
Sni 2011
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cevimelinecapsule30 mg/1oralRanbaxy Pharmaceuticals Inc.2012-10-07Not applicableUs
Cevimeline Hydrochloridecapsule30 mg/1oralAmerican Health Packaging2015-03-31Not applicableUs
Evoxaccapsule30 mg/1oralSTAT Rx USA LLC2000-01-11Not applicableUs
Evoxaccapsule30 mg/1oralDaiichi Sankyo Pharma Development2000-01-12Not applicableUs
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cevimeline Hydrochloridecapsule30 mg/1oralRoxane Laboratories, Inc.2013-07-08Not applicableUs
Cevimeline Hydrochloridecapsule30 mg/1oralAvera Mc Kennan Hospital2015-10-30Not applicableUs
Cevimeline Hydrochloridecapsule30 mg/1oralApotex Corp.2012-10-08Not applicableUs
Cevimeline Hydrochloridecapsule30 mg/1oralPACK Pharmaceuticals, LLC2014-06-17Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
SaligrenNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Cevimeline hydrochloride
Thumb
  • InChI Key: WUTYZMFRCNBCHQ-PSASIEDQSA-N
  • Monoisotopic Mass: 199.103084861
  • Average Mass: 199.313
DBSALT000805
Categories
UNIIK9V0CDQ56E
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as azaspirodecane derivatives. These are organic compounds containing a spirodecane moiety with at least one nitrogen atom.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassAzaspirodecane derivatives
Sub ClassNot Available
Direct ParentAzaspirodecane derivatives
Alternative Parents
Substituents
  • Azaspirodecane
  • Quinuclidine
  • Piperidine
  • Oxathiolane
  • Monothioacetal
  • Tertiary aliphatic amine
  • Tertiary amine
  • Oxacycle
  • Azacycle
  • Thioether
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External Descriptors
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.
Related Articles
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
Not Available
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
PropertyValueProbability
Human Intestinal Absorption+0.9899
Blood Brain Barrier+0.9823
Caco-2 permeable+0.6465
P-glycoprotein substrateSubstrate0.7063
P-glycoprotein inhibitor INon-inhibitor0.6941
P-glycoprotein inhibitor IINon-inhibitor0.9434
Renal organic cation transporterInhibitor0.6934
CYP450 2C9 substrateNon-substrate0.8083
CYP450 2D6 substrateSubstrate0.8918
CYP450 3A4 substrateSubstrate0.5719
CYP450 1A2 substrateNon-inhibitor0.8634
CYP450 2C9 inhibitorNon-inhibitor0.9047
CYP450 2D6 inhibitorNon-inhibitor0.6012
CYP450 2C19 inhibitorNon-inhibitor0.7312
CYP450 3A4 inhibitorNon-inhibitor0.9154
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7686
Ames testNon AMES toxic0.7969
CarcinogenicityNon-carcinogens0.9054
BiodegradationNot ready biodegradable0.9942
Rat acute toxicity2.7785 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6383
hERG inhibition (predictor II)Non-inhibitor0.8469
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Daiichi sankyo co ltd
Packagers
Dosage forms
FormRouteStrength
Capsuleoral30 mg/1
Prices
Unit descriptionCostUnit
Evoxac 30 mg capsule2.69USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US4855290 No1992-08-302009-08-30Us
US5340821 No1993-07-072013-07-07Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point201-203 °C (HCl salt)Not Available
water solubilityVery solubleNot Available
logP1.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.41 mg/mLALOGPS
logP1.46ALOGPS
logP1ChemAxon
logS-1.9ALOGPS
pKa (Strongest Basic)8.59ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity55.92 m3·mol-1ChemAxon
Polarizability21.89 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferencesNot Available
External Links
ATC CodesN07AX03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (34.3 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
Cimetropium BromideCevimeline may decrease the anticholinergic activities of Cimetropium Bromide.
NadololThe risk or severity of adverse effects can be increased when Nadolol is combined with Cevimeline.
TacrineThe risk or severity of adverse effects can be increased when Tacrine is combined with Cevimeline.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Receptor activity
Specific Function:
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.
Gene Name:
CHRM3
Uniprot ID:
P20309
Molecular Weight:
66127.445 Da
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:17139284 ]
  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:17016423 ]
  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. doi: 10.1152/ajpgi.00359.2007. Epub 2008 May 1. [PubMed:18450949 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Phosphatidylinositol phospholipase c activity
Specific Function:
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.
Gene Name:
CHRM1
Uniprot ID:
P11229
Molecular Weight:
51420.375 Da
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:17139284 ]
  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:17016423 ]
  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:8624083 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
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.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
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:11725960 ]
  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:12608011 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
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 xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
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:11725960 ]
  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:12608011 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Nadp binding
Specific Function:
This protein is involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. Form I catalyzes the N-oxygenation of secondary and tertiary amines.
Gene Name:
FMO1
Uniprot ID:
Q01740
Molecular Weight:
60310.285 Da
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:11725960 ]
  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:12608011 ]
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:08