Ibudilast

Description

Ibudilast is a leukomene antagonist and phosphodiesterase inhibitor useful in the treatment of bronchial asthma. It antagonizes leukotriene D4-induced contractions of guinea pig ileum and tracheal muscles in virro, and inhibits eosinophil accumulation in vivo.

Chemical Properties

White Solid

Originator

Kyorin (Japan)

Uses

a phosphodiesterase inhibitor with anti-inflammatory activity

Uses

A leukotriene D4 antagonist. Used as an antiallergic, antiasthmatic, and vasodilator (cerebral)

Uses

Inhibitors of phosphodiesterase 4 (PDE4), which catalyzes the hydrolysis of cAMP, have potential applications in a variety of diseases, including asthma. Ibudilast is an inhibitor of PDE4 (IC50 = 54-239 nM) that, at higher doses, also inhibits PDE3 and PDE5 (IC50 = 1,600-3,510 nM). Through this action, it suppresses the elaboration of mediators involved in asthma and inflammation.[Cayman Chemical]

Definition

ChEBI: Ibudilast is a pyrazolopyridine.

brand name

Ketas

Biological Activity

Phosphodiesterase inhibitor (IC 50 values are 53, 35, 48, 12 and 10 mM for PDE Ia, II, III, IV and V respectively). Inhibits platelet aggregation and is an orally-active cerebral vasodilator, bronchodilator and antiallergic agent.

Biochem/physiol Actions

Phosphodiesterase IV (PDE4) inhbitor. Inhibits platelet aggregation. Anti-asthma drug.

Synthesis

(b) Synthesis of 1-(2-isopropylpyrazolo[1,5-α]pyridin-3-yl)-2-methylpropan-1-one. The dried 1-amino-2-methylpyridinium iodide salt (113 g) from step (a) was suspended in isobutyric anhydride (515 g) in a round-bottomed flask fitted with a mechanical stirrer, followed by the addition of potassium carbonate (85 g) under stirring. The reaction mixture was heated to reflux for 8 h. After cooling to room temperature, water (10 mL) was added and potassium carbonate (10 g) was added in batches. After the initial vigorous reaction subsided, water (500 mL) and ethyl acetate (500 mL) were added, followed by the addition of potassium carbonate (280 g) in batches while continuous mechanical stirring was used to control foaming. The mixture was stirred at room temperature for 1 h. 50% sodium hydroxide solution (50 mL) was added and extracted with ethyl acetate (4 x 250 mL). The organic phases were combined and the solvents were evaporated to give a viscous oil, which was separated by high-vacuum distillation to give 25.2 g (32.9% yield) of 2-isopropylpyrazolo[1,5-α]pyridine (boiling point 45-75 °C/0.25-0.5 mmHg) and 60.4 g (51.3% yield) of 1-(2-isopropylpyrazolo[1,5-α]pyridin-3-yl)-2-methyl propan-1-one (boiling point 125-135°C/0.1 mmHg; melting point 53-55°C) (T. Irikura et al., U.S. Patent 3,850,941, November 26, 1974)

in vitro

ibudilast could potently inhibit purified human pde4a, 4b, 4c and 4d with ic50 values at 54, 65, 239 and 166 nm, respectively. ibudilast was also able to effectively block lps-induced tumor necrosis factor and n-formyl-metleu-phe-induced leukotriene b4 biosynthesis in human whole blood [1].

in vivo

rats received a daily oral administration of 10, 30 or 60 mg/kg ibudilast. results showed that in the vehicle-treated animals, white matter lesions and microglial activation occurred in the optic tract, internal capsule and corpus callosum. a low dose of ibudilast failed to suppress the white matter lesions and microglial activation, whereas a dose of either 30 or 60 mg/kg ibudilast ameliorated these lesions [2].

IC 50

54-239 nm

storage

Store at RT

References

[1] Y. KISHI. Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall.[J]. Cardiovascular drug reviews, 2006, 5 1: 215-225. DOI:10.1111/j.1527-3466.2001.tb00066.x
[2] TAKANOBU YAMAZAKI  Shigeki M  Tsuyoshi Anraku. Ibudilast, a mixed PDE3/4 inhibitor, causes a selective and nitric oxide/cGMP-independent relaxation of the intracranial vertebrobasilar artery[J]. European journal of pharmacology, 2011, 650 2: Pages 605-611. DOI:10.1016/j.ejphar.2010.10.033
[3] JORGE L. CUEVA VARGAS  Adriana D P  Nicolas Belforte. The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signaling[J]. Neurobiology of Disease, 2016, 93: Pages 156-171. DOI:10.1016/j.nbd.2016.05.002
[4] TETSUYA MIZUNO . Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia[J]. Neuropharmacology, 2004, 46 3: Pages 404-411. DOI:10.1016/j.neuropharm.2003.09.009
[5] ANNEMARIE LEDEBOER. Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes.[J]. Expert opinion on investigational drugs, 2007, 16 7: 935-950. DOI:10.1517/13543784.16.7.935