Ibudilast
[CAS# 50847-11-5]

Identification

• Classification: API >> Antiallergic >> Allergic reaction medium blocker
• Name: Ibudilast
• Synonyms: 3-Isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine; 2-Methyl-1-[2-(1-methylethyl)pyrazolo[1,5-a]pyridin-3-yl]-1-propanone; 2-Isopropyl-3-isobutyrylpyrazolo[1,5-a]pyridine
• Molecular Formula: C₁₄H₁₈N₂O
• Molecular Weight: 230.31
• CAS Registry Number: 50847-11-5
• EC Number: 637-150-7
• SMILES: CC(C)C1=NN2C=CC=CC2=C1C(=O)C(C)C

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Melting point: 56 °C (Expl.)
• Solubility: Soluble 100 mM (DMSO), 100 mM (ethanol) (Expl.)
• Index of refraction: 1.571 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319

Discovery and Applications

Ibudilast is a small-molecule pharmaceutical compound known primarily for its action as a non-selective phosphodiesterase (PDE) inhibitor and as a modulator of glial cell activity. It is chemically classified as a benzofuran derivative and is used in several countries, including Japan and South Korea, for the treatment of asthma and post-stroke complications. Its structure includes a benzofuran ring substituted with an amide and alkyl groups that contribute to its lipophilicity and oral bioavailability.

The compound was first developed in Japan during the 1970s by Nippon Kayaku Co., Ltd. as part of a broader research effort into anti-inflammatory agents targeting cyclic nucleotide metabolism. Ibudilast's inhibition of PDE enzymes increases intracellular levels of cyclic AMP (cAMP) and cyclic GMP (cGMP), which in turn mediate smooth muscle relaxation, bronchodilation, and modulation of inflammatory responses. Its activity is not limited to a single PDE isoform; rather, it exhibits moderate inhibition across several isoforms including PDE3, PDE4, PDE10, and PDE11.

In Japan, ibudilast has been approved under the trade name Ketas for the treatment of bronchial asthma, chronic cerebral circulation disorders, and as a preventive agent for secondary cerebral infarction. It improves blood flow by inhibiting platelet aggregation and promoting vasodilation, and its neuroprotective and anti-inflammatory properties are considered beneficial in the post-stroke rehabilitation setting. Its ability to inhibit glial cell activation also contributes to its neuroprotective potential by suppressing the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6.

Beyond its approved uses, ibudilast has attracted international research attention for its potential therapeutic applications in neuropathic pain, multiple sclerosis (MS), opioid withdrawal, and substance use disorders. Studies have shown that ibudilast can reduce opioid tolerance and dependence by inhibiting glial activation and suppressing neuroinflammation, mechanisms that differ from traditional opioid antagonists. It has been investigated in the United States under investigational new drug (IND) applications and orphan drug designations for conditions including progressive MS and opioid use disorder.

Ibudilast is typically administered orally in tablet or capsule form. It is rapidly absorbed and undergoes hepatic metabolism, with its pharmacokinetics influenced by enterohepatic circulation. The drug has a relatively long half-life, allowing for twice-daily dosing in clinical settings. Common side effects reported during its use include nausea, headache, and abdominal discomfort, though it is generally well tolerated.

Analytical methods for characterizing and quantifying ibudilast in pharmaceutical preparations include high-performance liquid chromatography (HPLC), mass spectrometry (MS), and infrared (IR) spectroscopy. The compound is a pale-yellow crystalline solid, sparingly soluble in water but readily soluble in organic solvents such as ethanol and methanol. Stability studies indicate that ibudilast is stable under standard storage conditions but should be protected from excessive heat and light.

In recent years, the compound has also been investigated for its potential use in treating amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and other neurodegenerative conditions. These studies are ongoing, and while ibudilast has not yet received regulatory approval in most Western countries, clinical trials continue to evaluate its efficacy and safety in diverse therapeutic areas.

In summary, ibudilast is a well-established phosphodiesterase inhibitor and glial modulator originally developed in Japan for asthma and cerebral circulation disorders. Its unique pharmacological profile has made it a subject of active investigation in neurology and addiction medicine. Its combination of anti-inflammatory, neuroprotective, and vasodilatory actions positions it as a candidate for expanded use in treating central nervous system disorders and inflammatory conditions.

References

2024. Targeting phosphodiesterase 4 as a potential therapy for Parkinson’s disease: a review. Molecular Biology Reports, 51(5).
DOI: 10.1007/s11033-024-09484-8

2024. Molecular Indicator for Distinguishing Multi-drug-Resistant Tuberculosis from Drug Sensitivity Tuberculosis and Potential Medications for Treatment. Molecular Biotechnology.
DOI: 10.1007/s12033-024-01299-z

2024. Morphine self-administration is inhibited by the antioxidant N-acetylcysteine and the anti-inflammatory ibudilast; an effect enhanced by their co-administration. PLOS ONE, 19(10).
DOI: 10.1371/journal.pone.0312828