Identification

Name
Ibudilast
Accession Number
DB05266  (DB05066)
Type
Small Molecule
Groups
Investigational
Description

Ibudilast is an anti-inflammatory and neuroprotective oral agent which shows an excellent safety profile at 60 mg/day and provides significantly prolonged time-to-first relapse and attenuated brain volume shrinkage in patients with relapsing-remitting (RR) and/or secondary progressive (SP) multiple sclerosis (MS). Ibudilast is currently in development in the U.S. (codes: AV-411 or MN-166), but is approved for use as an antiinflammatory in Japan.

Structure
Thumb
Synonyms
  • Ibudilastum
External IDs
AV-411 / AV411 / BRN 0656579 / MN-166
International/Other Brands
Ke Tas / Ketas
Categories
UNII
M0TTH61XC5
CAS number
50847-11-5
Weight
Average: 230.3055
Monoisotopic: 230.141913208
Chemical Formula
C14H18N2O
InChI Key
ZJVFLBOZORBYFE-UHFFFAOYSA-N
InChI
InChI=1S/C14H18N2O/c1-9(2)13-12(14(17)10(3)4)11-7-5-6-8-16(11)15-13/h5-10H,1-4H3
IUPAC Name
2-methyl-1-[2-(propan-2-yl)pyrazolo[1,5-a]pyridin-3-yl]propan-1-one
SMILES
CC(C)C(=O)C1=C2C=CC=CN2N=C1C(C)C

Pharmacology

Indication

For the treatment of multiple sclerosis, asthma, and cerebrovascular disease.

Pharmacodynamics
Not Available
Mechanism of action

Ibudilast has mechanisms that include anti-inflammatory effects, such as phosphodiesterase inhibition, and neuroprotective effects, such as inhibition of Nitric Oxide synthesis and reduction in reactive oxygen species.

TargetActionsOrganism
AcAMP-specific 3',5'-cyclic phosphodiesterase 4A
inhibitor
Human
AcAMP-specific 3',5'-cyclic phosphodiesterase 4B
inhibitor
Human
AcAMP-specific 3',5'-cyclic phosphodiesterase 4C
inhibitor
Human
UcAMP-specific 3',5'-cyclic phosphodiesterase 4D
inhibitor
Human
UcGMP-inhibited 3',5'-cyclic phosphodiesterase A
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

19 hours

Clearance
Not Available
Toxicity

Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Ibudilast is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Ibudilast is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Ibudilast is combined with 4-hydroxycoumarin.
AbciximabIbudilast may increase the anticoagulant activities of Abciximab.
AcenocoumarolThe risk or severity of bleeding can be increased when Ibudilast is combined with Acenocoumarol.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Ibudilast is combined with Acetylsalicylic acid.
AlaproclateThe risk or severity of hemorrhage can be increased when Alaproclate is combined with Ibudilast.
AldesleukinThe risk or severity of bleeding can be increased when Ibudilast is combined with Aldesleukin.
AlemtuzumabThe risk or severity of bleeding can be increased when Ibudilast is combined with Alemtuzumab.
AloxiprinThe risk or severity of adverse effects can be increased when Ibudilast is combined with Aloxiprin.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0015614
PubChem Compound
3671
PubChem Substance
99443231
ChemSpider
3543
BindingDB
50240404
ChEBI
31684
ChEMBL
CHEMBL19449
PharmGKB
PA165958351
HET
AVL
Wikipedia
Ibudilast
ATC Codes
R03DC04 — Ibudilast
PDB Entries
4grq

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingOtherHealthy Volunteers1
1CompletedNot AvailableMethamphetamine-dependence / Substance Abuse1
1CompletedBasic ScienceMigrainous Headache1
1CompletedTreatmentAlcohol Use Disorders (AUD)1
1, 2Active Not RecruitingTreatmentAmyotrophic Lateral Sclerosis (ALS)1
1, 2CompletedTreatmentDiabetic Neuropathies1
1, 2Unknown StatusTreatmentMedication Overuse Headache1
2Active Not RecruitingNot AvailableOpioid Abuse / Opioid Dependence1
2CompletedBasic ScienceOpioid-Related Disorders1
2CompletedTreatmentAmyotrophic Lateral Sclerosis (ALS)1
2CompletedTreatmentMultiple Sclerosis, Primary Progressive / Secondary Progressive Multiple Sclerosis (SPMS)1
2Not Yet RecruitingTreatmentMethamphetamine Dependence in Remission1
2RecruitingTreatmentAlcohol Use Disorder (AUD)2
2RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections / Methamphetamine Dependence1

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 Solubility0.179 mg/mLALOGPS
logP3.36ALOGPS
logP3.68ChemAxon
logS-3.1ALOGPS
pKa (Strongest Acidic)16.12ChemAxon
pKa (Strongest Basic)1.86ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area34.37 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity79.38 m3·mol-1ChemAxon
Polarizability26.31 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9868
Caco-2 permeable+0.6112
P-glycoprotein substrateNon-substrate0.788
P-glycoprotein inhibitor IInhibitor0.5207
P-glycoprotein inhibitor IINon-inhibitor0.7071
Renal organic cation transporterNon-inhibitor0.8179
CYP450 2C9 substrateNon-substrate0.8076
CYP450 2D6 substrateNon-substrate0.793
CYP450 3A4 substrateSubstrate0.5476
CYP450 1A2 substrateInhibitor0.9106
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorInhibitor0.6259
CYP450 2C19 inhibitorInhibitor0.8071
CYP450 3A4 inhibitorNon-inhibitor0.6338
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7965
Ames testNon AMES toxic0.7408
CarcinogenicityNon-carcinogens0.8482
BiodegradationNot ready biodegradable0.9838
Rat acute toxicity2.2040 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9554
hERG inhibition (predictor II)Non-inhibitor0.9088
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 GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000w-3910000000-7c4d5c86420e4e74cdb1

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyrazolopyridines. These are compounds containing a pyrazolopyridine skeleton, which consists of a pyrazole fused to a pyridine. Pyrazole is 5-membered ring consisting of three carbon atoms and two adjacent nitrogen centers. Pyridine is a 6-membered ring with four carbon and one nitrogen atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyrazolopyridines
Sub Class
Not Available
Direct Parent
Pyrazolopyridines
Alternative Parents
Aryl alkyl ketones / Pyridines and derivatives / Vinylogous amides / Pyrazoles / Heteroaromatic compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Pyrazolopyridine / Aryl alkyl ketone / Aryl ketone / Pyridine / Azole / Pyrazole / Heteroaromatic compound / Vinylogous amide / Ketone / Azacycle
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

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.
Gene Name
PDE4A
Uniprot ID
P27815
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4A
Molecular Weight
98142.155 Da
References
  1. Yagi K, Tada Y, Kitazato KT, Tamura T, Satomi J, Nagahiro S: Ibudilast inhibits cerebral aneurysms by down-regulating inflammation-related molecules in the vascular wall of rats. Neurosurgery. 2010 Mar;66(3):551-9; discussion 559. doi: 10.1227/01.NEU.0000365771.89576.77. [PubMed:20124930]
  2. Yamazaki T, Anraku T, Matsuzawa S: Ibudilast, a mixed PDE3/4 inhibitor, causes a selective and nitric oxide/cGMP-independent relaxation of the intracranial vertebrobasilar artery. Eur J Pharmacol. 2011 Jan 15;650(2-3):605-11. doi: 10.1016/j.ejphar.2010.10.033. Epub 2010 Oct 29. [PubMed:21036126]
  3. Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K: Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sci. 2006 May 1;78(23):2663-8. Epub 2005 Nov 28. [PubMed:16313925]
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. Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K: Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sci. 2006 May 1;78(23):2663-8. Epub 2005 Nov 28. [PubMed:16313925]
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.
Gene Name
PDE4C
Uniprot ID
Q08493
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4C
Molecular Weight
79900.795 Da
References
  1. Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K: Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sci. 2006 May 1;78(23):2663-8. Epub 2005 Nov 28. [PubMed:16313925]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K: Preferential inhibition of human phosphodiesterase 4 by ibudilast. Life Sci. 2006 May 1;78(23):2663-8. Epub 2005 Nov 28. [PubMed:16313925]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
Gene Name
PDE3A
Uniprot ID
Q14432
Uniprot Name
cGMP-inhibited 3',5'-cyclic phosphodiesterase A
Molecular Weight
124978.06 Da
References
  1. Yamazaki T, Anraku T, Matsuzawa S: Ibudilast, a mixed PDE3/4 inhibitor, causes a selective and nitric oxide/cGMP-independent relaxation of the intracranial vertebrobasilar artery. Eur J Pharmacol. 2011 Jan 15;650(2-3):605-11. doi: 10.1016/j.ejphar.2010.10.033. Epub 2010 Oct 29. [PubMed:21036126]

Drug created on November 18, 2007 11:22 / Updated on November 02, 2018 06:09