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{{Short description|Chemical compound}}
{{Drugbox {{Drugbox
| Verifiedfields = changed
⚫ | IUPAC_name = 2-methyl-1-(2-propan-2-ylpyrazolopyridin-3-yl)propan-1-one
| Watchedfields = changed
⚫ | image = Ibudilast.svg
| verifiedrevid = 407396353
⚫ | CAS_number = 50847-11-5
⚫ | IUPAC_name = 2-Methyl-1-(2-propan-2-ylpyrazolopyridin-3-yl)propan-1-one
⚫ | ATC_prefix = R03
⚫ | image = Ibudilast.svg
⚫ | ATC_suffix = DC04
| width = 150
⚫ | PubChem = 3671

⚫ | DrugBank =
<!--Clinical data-->
| tradename = Ketas, Pinatos, Eyevinal
| Drugs.com = {{drugs.com|international|ibudilast}}
⚫ | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
⚫ | pregnancy_US = <!-- A / B / C / D / X -->
⚫ | pregnancy_category =
⚫ | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
⚫ | legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
⚫ | legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
⚫ | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = Rx-only <small>(] ])</small>
| routes_of_administration = ] (]),<br /> ] (])

<!--Pharmacokinetic data-->
⚫ | bioavailability =
⚫ | protein_bound =
| metabolism =
⚫ | elimination_half-life =
⚫ | excretion =

<!--Identifiers-->
| IUPHAR_ligand = 7399
| CAS_number_Ref = {{cascite|correct|??}}
⚫ | CAS_number = 50847-11-5
⚫ | ATC_prefix = R03
⚫ | ATC_suffix = DC04
⚫ | PubChem = 3671
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
⚫ | DrugBank = DB05266
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 3543
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = M0TTH61XC5
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01385 | KEGG = D01385
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| C=14|H=18|N=2|O=1
| ChEMBL = 19449
| molecular_weight = 230.31 g/mol

⚫ | bioavailability =
<!--Chemical data-->
⚫ | protein_bound =
| metabolism = | C=14 | H=18 | N=2 | O=1
| SMILES = CC(C)C(=O)c1c(nn2ccccc12)C(C)C
⚫ | elimination_half-life =
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
⚫ | excretion =
| StdInChI = 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
⚫ | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
⚫ | pregnancy_US = <!-- A / B / C / D / X -->
| StdInChIKey = ZJVFLBOZORBYFE-UHFFFAOYSA-N
⚫ | pregnancy_category=
⚫ | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
⚫ | legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
⚫ | legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
⚫ | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status =
| routes_of_administration =
}} }}


'''Ibudilast''' (current development codes: '''AV-411''' or '''MN-166''') is an ] drug used mainly in Japan, which acts as a ], inhibiting the PDE-4 subtype to the greatest extent,<ref>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 Sciences''. 2006 May 1;78(23):2663-8.</ref> but also showing significant inhibition of other PDE subtypes.<ref>Suzumura A, Ito A, Yoshikawa M, Sawada M. Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. ''Brain Research''. 1999 Aug 7;837(1-2):203-12.</ref><ref>Gibson LC, Hastings SF, McPhee I, Clayton RA, Darroch CE, Mackenzie A, Mackenzie FL, Nagasawa M, Stevens PA, Mackenzie SJ. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. ''European Journal of Pharmacology''. 2006 May 24;538(1-3):39-42.</ref> '''Ibudilast ''' (development codes: '''AV-411''' or '''MN-166''') is an ] drug used mainly in Japan, which acts as a ], inhibiting the ] subtype to the greatest extent,<ref>{{cite journal | vauthors = Huang Z, Liu S, Zhang L, Salem M, Greig GM, Chan CC, Natsumeda Y, Noguchi K | display-authors = 6 | title = Preferential inhibition of human phosphodiesterase 4 by ibudilast | journal = Life Sciences | volume = 78 | issue = 23 | pages = 2663–2668 | date = May 2006 | pmid = 16313925 | doi = 10.1016/j.lfs.2005.10.026 }}</ref> but also showing significant inhibition of other PDE subtypes.<ref>{{cite journal | vauthors = Suzumura A, Ito A, Yoshikawa M, Sawada M | title = Ibudilast suppresses TNFalpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS | journal = Brain Research | volume = 837 | issue = 1–2 | pages = 203–212 | date = August 1999 | pmid = 10434004 | doi = 10.1016/s0006-8993(99)01666-2 | s2cid = 7910607 }}</ref><ref>{{cite journal | vauthors = Gibson LC, Hastings SF, McPhee I, Clayton RA, Darroch CE, Mackenzie A, Mackenzie FL, Nagasawa M, Stevens PA, Mackenzie SJ | display-authors = 6 | title = The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family | journal = European Journal of Pharmacology | volume = 538 | issue = 1–3 | pages = 39–42 | date = May 2006 | pmid = 16674936 | doi = 10.1016/j.ejphar.2006.02.053 }}</ref>

==Medical uses==
In ], ibudilast oral capsules are approved for the treatment of ], and for improvement of ] secondary to chronic cerebral circulation impairment associated with sequelae of ].<ref name="Ketas PI">{{cite web|title=Ketas (ibudilast) Capsules 10 mg. Prescribing Information|url=http://www.kyorin-pharm.co.jp/prodinfo/medicine/pdf/KETAS_Capsules.pdf|publisher=Kyorin Pharmaceutical Co., Ltd.|access-date=3 October 2016|archive-date=30 August 2018|archive-url=https://web.archive.org/web/20180830210732/http://www.kyorin-pharm.co.jp/prodinfo/medicine/pdf/KETAS_Capsules.pdf|url-status=dead}}</ref> Ibudilast ophthalmic solution is indicated for the treatment of ] and ].<ref>{{cite web|title=Ketas (ibudilast) Eye Drops 0.01% Kisuri-no-Shiori (Drug Information Sheet)|url=http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=1744|publisher=Senju Pharmaceutical Co., Ltd.|access-date=3 October 2016}}</ref>

It may have some use reducing methamphetamine,<ref>{{Cite web |url=http://www.huffingtonpost.com/2013/04/03/meth-addiction-cure-ucla-ibudilast_n_2863126.html | title=Cure for Meth Addiction?| website=]| date=2013-04-03}}</ref><ref>{{cite journal | vauthors = Chand S, Gowen A, Savine M, Moore D, Clark A, Huynh W, Wu N, Odegaard K, Weyrich L, Bevins RA, Fox HS, Pendyala G, Yelamanchili SV | display-authors = 6 | title = A comprehensive study to delineate the role of an extracellular vesicle-associated microRNA-29a in chronic methamphetamine use disorder | journal = Journal of Extracellular Vesicles | volume = 10 | issue = 14 | pages = e12177 | date = December 2021 | pmid = 34913274 | doi = 10.1002/jev2.12177 | pmc = 8674191 }}</ref> opioid,<ref>{{cite journal | vauthors = Cooper ZD, Johnson KW, Pavlicova M, Glass A, Vosburg SK, Sullivan MA, Manubay JM, Martinez DM, Jones JD, Saccone PA, Comer SD | display-authors = 6 | title = The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid-dependent volunteers | journal = Addiction Biology | volume = 21 | issue = 4 | pages = 895–903 | date = July 2016 | pmid = 25975386 | pmc = 4644513 | doi = 10.1111/adb.12261 }}</ref> and alcohol<ref>{{cite journal | vauthors = Bell RL, Lopez MF, Cui C, Egli M, Johnson KW, Franklin KM, Becker HC | title = Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence | journal = Addiction Biology | volume = 20 | issue = 1 | pages = 38–42 | date = January 2015 | pmid = 24215262 | pmc = 4017009 | doi = 10.1111/adb.12106 }}</ref> addiction.

==Pharmacology==
⚫ Ibudilast has ], ]<ref>{{cite journal | vauthors = Kishi Y, Ohta S, Kasuya N, Sakita S, Ashikaga T, Isobe M | title = Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall | journal = Cardiovascular Drug Reviews | volume = 19 | issue = 3 | pages = 215–225 | date = Fall 2001 | pmid = 11607039 | doi = 10.1111/j.1527-3466.2001.tb00066.x }}</ref> and ] effects,<ref>{{cite journal | vauthors = Mizuno T, Kurotani T, Komatsu Y, Kawanokuchi J, Kato H, Mitsuma N, Suzumura A | title = Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia | journal = Neuropharmacology | volume = 46 | issue = 3 | pages = 404–411 | date = March 2004 | pmid = 14975696 | doi = 10.1016/j.neuropharm.2003.09.009 | s2cid = 29284554 }}</ref><ref>{{cite journal | vauthors = Yoshioka M, Suda N, Mori K, Ueno K, Itoh Y, Togashi H, Matsumoto M | title = Effects of ibudilast on hippocampal long-term potentiation and passive avoidance responses in rats with transient cerebral ischemia | journal = Pharmacological Research | volume = 45 | issue = 4 | pages = 305–311 | date = April 2002 | pmid = 12030794 | doi = 10.1006/phrs.2002.0949 }}</ref> and is mainly used in the treatment of ] and ].<ref>{{cite journal | vauthors = Wakita H, Tomimoto H, Akiguchi I, Lin JX, Ihara M, Ohtani R, Shibata M | title = Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat | journal = Brain Research | volume = 992 | issue = 1 | pages = 53–59 | date = November 2003 | pmid = 14604772 | doi = 10.1016/j.brainres.2003.08.028 | s2cid = 24917936 }}</ref> It inhibits ] aggregation,<ref>{{cite journal | vauthors = Rile G, Yatomi Y, Qi R, Satoh K, Ozaki Y | title = Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells | journal = Thrombosis Research | volume = 102 | issue = 3 | pages = 239–246 | date = May 2001 | pmid = 11369417 | doi = 10.1016/s0049-3848(01)00258-4 }}</ref> and may also be useful in the treatment of ].<ref>{{cite journal | vauthors = Feng J, Misu T, Fujihara K, Sakoda S, Nakatsuji Y, Fukaura H, Kikuchi S, Tashiro K, Suzumura A, Ishii N, Sugamura K, Nakashima I, Itoyama Y | display-authors = 6 | title = Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis | journal = Multiple Sclerosis | volume = 10 | issue = 5 | pages = 494–498 | date = October 2004 | pmid = 15471363 | doi = 10.1191/1352458504ms1070oa | s2cid = 34072005 }}</ref>


⚫ Ibudilast crosses the ] and suppresses ] activation. This activity has been shown to make ibudilast useful in the treatment of ] and it not only enhances ] produced by ] drugs, but also reduces the development of ].<ref>{{cite journal | vauthors = Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW | title = Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes | journal = Expert Opinion on Investigational Drugs | volume = 16 | issue = 7 | pages = 935–950 | date = July 2007 | pmid = 17594181 | doi = 10.1517/13543784.16.7.935 | s2cid = 22321634 }}</ref>
⚫ Ibudilast has ], ] <ref>Kishi Y, Ohta S, Kasuya N, Sakita S, Ashikaga T, Isobe M. Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall. ''Cardiovascular Drug Reviews''. 2001 Fall;19(3):215-25.</ref> and ] effects,<ref>Mizuno T, Kurotani T, Komatsu Y, Kawanokuchi J, Kato H, Mitsuma N, Suzumura A. Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. ''Neuropharmacology''. 2004 Mar;46(3):404-11.</ref><ref>Yoshioka M, Suda N, Mori K, Ueno K, Itoh Y, Togashi H, Matsumoto M. Effects of ibudilast on hippocampal long-term potentiation and passive avoidance responses in rats with transient cerebral ischemia. ''Pharmacological Research''. 2002 Apr;45(4):305-11.</ref> and is mainly used in the treatment of ] and ].<ref>Wakita H, Tomimoto H, Akiguchi I, Lin JX, Ihara M, Ohtani R, Shibata M. Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. ''Brain Research''. 2003 Nov 28;992(1):53-9.</ref> It inhibits ] aggregation,<ref>Rile G, Yatomi Y, Qi R, Satoh K, Ozaki Y. Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells. ''Thrombosis Research''. 2001 May 1;102(3):239-46.</ref> and may also be useful in the treatment of ].<ref>Feng J, Misu T, Fujihara K, Sakoda S, Nakatsuji Y, Fukaura H, Kikuchi S, Tashiro K, Suzumura A, Ishii N, Sugamura K, Nakashima I, Itoyama Y. Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. ''Multiple Sclerosis''. 2004 Oct;10(5):494-8.</ref>


===Pharmacodynamics===
⚫ Ibudilast crosses the ] and suppresses ] activation. This activity has been shown to make ibudilast useful in the treatment of ] and it not only enhances ] produced by ] drugs, but also reduces the development of ].<ref>Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. ''Expert Opinion on Investigational Drugs''. 2007 Jul;16(7):935-50.</ref>
Ibudilast is principally a PDE4 inhibitor, but it also has significant affinity for PDE3, PDE10A, PDE11.<ref>Gibson L.C., Hastings S.F., McPhee I., Clayton r.A., Darroch C.E., Mackenzie A., Mackenzie F.L., Nagasawa M., Stevens P.A., Macken‑ zie S.J.: The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. Eur. J. Pharmacol., 2006; 538: 39‑42</ref> Ibudilast has also been shown to act as an ] at the ] 4 (]).<ref>{{cite journal | vauthors = Jia ZJ, Wu FX, Huang QH, Liu JM | title = | journal = Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae | volume = 34 | issue = 2 | pages = 168–173 | date = April 2012 | pmid = 22776604 | doi = 10.3881/j.issn.1000-503X.2012.02.013 }}</ref> This likely plays a large part in its effect, specifically its synergy with opioid drugs, its ] effect, and its own ] effect.<ref>{{cite journal | vauthors = Hutchinson MR, Zhang Y, Shridhar M, Evans JH, Buchanan MM, Zhao TX, Slivka PF, Coats BD, Rezvani N, Wieseler J, Hughes TS, Landgraf KE, Chan S, Fong S, Phipps S, Falke JJ, Leinwand LA, Maier SF, Yin H, Rice KC, Watkins LR | display-authors = 6 | title = Evidence that opioids may have toll-like receptor 4 and MD-2 effects | journal = Brain, Behavior, and Immunity | volume = 24 | issue = 1 | pages = 83–95 | date = January 2010 | pmid = 19679181 | pmc = 2788078 | doi = 10.1016/j.bbi.2009.08.004 }}</ref> It is unknown if the PDE4-inhibiting properties ] the effects of TLR4 inactivation and/or vice versa, despite that some of their effects are shared, such as ] reducing properties.<ref>{{cite journal | vauthors = Jin SL, Ding SL, Lin SC | title = Phosphodiesterase 4 and its inhibitors in inflammatory diseases | journal = Chang Gung Medical Journal | volume = 35 | issue = 3 | pages = 197–210 | date = 2012-06-01 | pmid = 22735051 | doi = 10.4103/2319-4170.106152 | doi-access = free }}</ref> TLR4 antagonists theoretically reverse the increase in pain and inflammation caused by most TLR4 ]s, which includes alcohol & many ] or ] drugs.<ref>{{cite journal | vauthors = Komatsu T, Sakurada S, Katsuyama S, Sanai K, Sakurada T | title = Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice | journal = International Review of Neurobiology | volume = 85 | pages = 207–219 | date = 2009-01-01 | pmid = 19607972 | doi = 10.1016/S0074-7742(09)85016-2 }}</ref>
{{clear}}


==References== == References ==
{{reflist}} {{reflist|32em}}


{{Drugs for obstructive airway diseases}}
{{Phosphodiesterase inhibitors}} {{Phosphodiesterase inhibitors}}