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Identification
NameCilomilast
Accession NumberDB03849  (EXPT00920)
TypeSmall Molecule
GroupsInvestigational
DescriptionCilomilast (Ariflo, SB-207,499) is a drug which was developed for the treatment of respiratory disorders such as asthma and Chronic Obstructive Pulmonary Disease (COPD). It is orally active and acts as a selective Phosphodiesterase-4 inhibitor. Following four clinical trials, the drug proved to be effective in treating COPD, however it has never been marketed due to a poor side effect profile.
Structure
Thumb
Synonyms
Ariflo
cis-4-cyano-4-(3-(cyclopentyloxy)-4-methoxyphenyl)cyclohexanecarboxylic acid
External Identifiers
  • SB 207499
  • SB-207,499
  • SB-207499
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII8ATB1C1R6X
CAS number153259-65-5
WeightAverage: 343.4168
Monoisotopic: 343.178358293
Chemical FormulaC20H25NO4
InChI KeyCFBUZOUXXHZCFB-OYOVHJISSA-N
InChI
InChI=1S/C20H25NO4/c1-24-17-7-6-15(12-18(17)25-16-4-2-3-5-16)20(13-21)10-8-14(9-11-20)19(22)23/h6-7,12,14,16H,2-5,8-11H2,1H3,(H,22,23)/t14-,20-
IUPAC Name
(1s,4s)-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic acid
SMILES
[H][C@@]1(CC[C@](CC1)(C#N)C1=CC(OC2CCCC2)=C(OC)C=C1)C(O)=O
Pharmacology
IndicationInvestigated for use/treatment in chronic obstructive pulmonary disease (COPD).
Structured Indications Not Available
PharmacodynamicsNot Available
Mechanism of actionCilomilast shows high selectivity for cAMP-specific PDE4, an isoenzyme that predominates in pro-inflammatory and immune cells and that is 10-fold more selective for PDE4D than for PDE4A, -B or -C. In vitro, cilomilast suppresses the activity of several pro-inflammatory and immune cells that have been implicated in the pathogenesis of asthma and COPD. Moreover, it is highly active in animal models of these diseases. Cilomilast has been shown to exert potent anti-inflammatory effects both in vitro and in vivo.
TargetKindPharmacological actionActionsOrganismUniProt ID
cAMP-specific 3',5'-cyclic phosphodiesterase 4DProteinyes
inhibitor
HumanQ08499 details
cAMP-specific 3',5'-cyclic phosphodiesterase 4BProteinyes
inhibitor
HumanQ07343 details
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organismsNot Available
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available
References
Synthesis Reference

Christensen, Siegfried B.; Guider, Aimee; Forster, Cornelia J.; Gleason, John G.; Bender, Paul E.; Karpinski, Joseph M.; Dewolf,, Walter E.; Barnette, Mary S.; et al. (1998). “1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma”. Journal of Medicinal Chemistry 41 (6): 821–35.

General References
  1. Torphy TJ, Barnette MS, Underwood DC, Griswold DE, Christensen SB, Murdoch RD, Nieman RB, Compton CH: Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulm Pharmacol Ther. 1999;12(2):131-5. [PubMed:10373396 ]
  2. Ochiai H, Ohtani T, Ishida A, Kusumi K, Kato M, Kohno H, Kishikawa K, Obata T, Nakai H, Toda M: Highly potent PDE4 inhibitors with therapeutic potential. Bioorg Med Chem Lett. 2004 Jan 5;14(1):207-10. [PubMed:14684329 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9742
Blood Brain Barrier+0.8165
Caco-2 permeable+0.5624
P-glycoprotein substrateNon-substrate0.5848
P-glycoprotein inhibitor INon-inhibitor0.6738
P-glycoprotein inhibitor IINon-inhibitor0.6658
Renal organic cation transporterNon-inhibitor0.7946
CYP450 2C9 substrateNon-substrate0.709
CYP450 2D6 substrateNon-substrate0.8309
CYP450 3A4 substrateSubstrate0.6456
CYP450 1A2 substrateNon-inhibitor0.5574
CYP450 2C9 inhibitorNon-inhibitor0.5812
CYP450 2D6 inhibitorNon-inhibitor0.9383
CYP450 2C19 inhibitorNon-inhibitor0.5328
CYP450 3A4 inhibitorNon-inhibitor0.6644
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7841
Ames testNon AMES toxic0.8722
CarcinogenicityNon-carcinogens0.9202
BiodegradationNot ready biodegradable0.681
Rat acute toxicity2.7220 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9728
hERG inhibition (predictor II)Non-inhibitor0.7201
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0155 mg/mLALOGPS
logP3.91ALOGPS
logP3.9ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)2.33ChemAxon
pKa (Strongest Basic)-4.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area79.55 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity93 m3·mol-1ChemAxon
Polarizability37.25 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
ClassificationNot classified

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Ubiquitin protein ligase binding
Specific Function:
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name:
PDE4D
Uniprot ID:
Q08499
Molecular Weight:
91114.1 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235 ]
  2. Kroegel C, Foerster M: Phosphodiesterase-4 inhibitors as a novel approach for the treatment of respiratory disease: cilomilast. Expert Opin Investig Drugs. 2007 Jan;16(1):109-24. [PubMed:17155857 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Metal ion binding
Specific Function:
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.
Gene Name:
PDE4B
Uniprot ID:
Q07343
Molecular Weight:
83342.695 Da
References
  1. Kroegel C, Foerster M: Phosphodiesterase-4 inhibitors as a novel approach for the treatment of respiratory disease: cilomilast. Expert Opin Investig Drugs. 2007 Jan;16(1):109-24. [PubMed:17155857 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23