Identification

Name
Cilomilast
Accession Number
DB03849  (EXPT00920)
Type
Small Molecule
Groups
Investigational
Description

Cilomilast (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 IDs
SB 207499 / SB-207,499 / SB-207499
Categories
UNII
8ATB1C1R6X
CAS number
153259-65-5
Weight
Average: 343.4168
Monoisotopic: 343.178358293
Chemical Formula
C20H25NO4
InChI Key
CFBUZOUXXHZCFB-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][[email protected]@]1(CC[[email protected]](CC1)(C#N)C1=CC(OC2CCCC2)=C(OC)C=C1)C(O)=O

Pharmacology

Indication

Investigated for use/treatment in chronic obstructive pulmonary disease (COPD).

Structured Indications
Not Available
Pharmacodynamics
Not Available
Mechanism of action

Cilomilast 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.

TargetActionsOrganism
AcAMP-specific 3',5'-cyclic phosphodiesterase 4D
inhibitor
Human
AcAMP-specific 3',5'-cyclic phosphodiesterase 4B
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not 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
KEGG Drug
D01704
PubChem Compound
151170
PubChem Substance
46505062
ChemSpider
18826005
BindingDB
50346088
ChEMBL
CHEMBL511115
HET
CIO
Wikipedia
Cilomilast
PDB Entries
1xlx / 1xom

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentBronchitis / Emphysema / Pulmonary Disease, Chronic Obstructive1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0155 mg/mLALOGPS
logP3.91ALOGPS
logP3.9ChemAxon
logS-4.4ALOGPS
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as anisoles. These are organic compounds containing a methoxybenzene or a derivative thereof.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenol ethers
Sub Class
Anisoles
Direct Parent
Anisoles
Alternative Parents
Phenoxy compounds / Methoxybenzenes / Alkyl aryl ethers / Nitriles / Monocarboxylic acids and derivatives / Carboxylic acids / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Phenoxy compound / Anisole / Methoxybenzene / Alkyl aryl ether / Monocyclic benzene moiety / Carboxylic acid derivative / Carboxylic acid / Ether / Monocarboxylic acid or derivatives / Carbonitrile
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

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
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4D
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 f...
Gene Name
PDE4B
Uniprot ID
Q07343
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4B
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]

Drug created on June 13, 2005 07:24 / Updated on December 01, 2017 15:19