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{{Short description|Chemical compound}} |
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{{Drugbox |
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{{Drugbox |
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| IUPAC_name = 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid |
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| image = Cilomilast.png |
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| verifiedrevid = 398754453 |
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| CAS_number = |
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| IUPAC_name = ''cis''-4-cyano-4-cyclohexanecarboxylic acid |
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| ATC_prefix = none |
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| image = Cilomilast.svg |
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| ATC_suffix = |
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| width = 250 |
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| PubChem = 151170 |
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| DrugBank = |
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<!--Clinical data--> |
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| C=20|H=25|N=1|O=4 |
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| tradename = |
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| molecular_weight = 343.417 g/mol |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| smiles = COC1=C(C=C(C=C1)C2(CCC(CC2)C(=O)O)C#N)OC3CCCC3 |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| bioavailability = |
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| pregnancy_category = |
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| protein_bound = |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| metabolism = |
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| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| elimination_half-life = |
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| excretion = |
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
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| legal_US_comment = Not approved |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| legal_status = |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| routes_of_administration = ] (]) |
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| pregnancy_category= |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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<!--Pharmacokinetic data--> |
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| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| bioavailability = |
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| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C --> |
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| protein_bound = |
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
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| legal_status = |
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| metabolism = |
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| elimination_half-life = |
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| routes_of_administration = |
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<!--Identifiers--> |
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| IUPHAR_ligand = 7407 |
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| CAS_number_Ref = {{cascite|changed|??}} |
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| CAS_number = 153259-65-5 |
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| ATC_prefix = None |
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| ATC_suffix = |
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| PubChem = 151170 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII = 8ATB1C1R6X |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL = 511115 |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| ChemSpiderID = 18826005 |
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| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChI = 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- |
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChIKey = CFBUZOUXXHZCFB-OYOVHJISSA-N |
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<!--Chemical data--> |
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| C=20 | H=25 | N=1 | O=4 |
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| smiles = COC1=C(C=C(C=C1)C2(CCC(CC2)C(=O)O)C#N)OC3CCCC3 |
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'''Cilomilast''' ('''Ariflo''', '''SB-207,499''') is a drug which was developed for the treatment of respiratory disorders such as ] and ] (COPD). It is orally active and acts as a selective ].<ref>http://www.medscape.com/viewarticle/549357</ref> |
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'''Cilomilast''' (],<ref>{{cite web|title=International Nonproprietary Names for Pharmaceutical Substances (INN) | work = Recommended International Nonproprietary Names (Rec. INN): List 44|url=https://www.who.int/medicines/publications/druginformation/innlists/RL44.pdf|publisher=World Health Organization|access-date=3 October 2016|page=188}}</ref> codenamed SB-207,499, proposed trade name '''Ariflo''') is a drug which was developed for the treatment of respiratory disorders such as ] and ] (COPD). It is orally active and acts as a selective ].<ref name="pmid16985092">{{cite journal | vauthors = Martina SD, Ismail MS, Vesta KS | title = Cilomilast: orally active selective phosphodiesterase-4 inhibitor for treatment of chronic obstructive pulmonary disease | journal = The Annals of Pharmacotherapy | volume = 40 | issue = 10 | pages = 1822–8 | date = October 2006 | pmid = 16985092 | doi = 10.1345/aph.1H049 | s2cid = 23187911 | url = http://www.medscape.com/viewarticle/549357 }}</ref> |
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] (PDE) inhibitors, such as ], have been used to treat ] for centuries; however, the clinical benefits of these agents have never been shown to out-weigh the risks of their numerous adverse effects. Four clinical trials were identified evaluating the efficacy of cilomilast, the usual randomized, double-blind, and placebo-controlled protocols were used. It showed reasonable efficacy for treating COPD, but side effects were problematic and it is unclear whether cilomalast will be marketed, or merely used in the development of newer drugs.<ref>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. ''Pulmonary Pharmacology and Therapeutics''. 1999;12(2):131-5. PMID 10373396</ref><ref>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. ''Bioorganic and Medicinal Chemistry Letters''. 2004 Jan 5;14(1):207-10. PMID 14684329</ref> |
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] (PDE) inhibitors, such as ], have been used to treat COPD for centuries; however, the clinical benefits of these agents have never been shown to outweigh the risks of their numerous adverse effects. Four clinical trials were identified evaluating the efficacy of cilomilast, the usual randomized, double-blind, and placebo-controlled protocols were used. It showed reasonable efficacy for treating COPD, but side effects were problematic and it is unclear whether cilomilast will be marketed, or merely used in the development of newer drugs.<ref name="pmid10373396">{{cite journal | vauthors = Torphy TJ, Barnette MS, Underwood DC, Griswold DE, Christensen SB, Murdoch RD, Nieman RB, Compton CH | display-authors = 6 | title = Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic | journal = Pulmonary Pharmacology & Therapeutics | volume = 12 | issue = 2 | pages = 131–5 | date = 1999 | pmid = 10373396 | doi = 10.1006/pupt.1999.0181 }}</ref><ref name="pmid14684329">{{cite journal | vauthors = Ochiai H, Ohtani T, Ishida A, Kusumi K, Kato M, Kohno H, Kishikawa K, Obata T, Nakai H, Toda M | display-authors = 6 | title = Highly potent PDE4 inhibitors with therapeutic potential | journal = Bioorganic & Medicinal Chemistry Letters | volume = 14 | issue = 1 | pages = 207–10 | date = January 2004 | pmid = 14684329 | doi = 10.1016/j.bmcl.2003.09.087 }}</ref> |
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Cilomilast is a second-generation PDE4 inhibitor with ] effects that target ], ] hypersecretion, and airway remodeling associated with COPD. |
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==History== |
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] (GSK) filed for drug approval with the ] at the end of 2002 and in January 2003 with the ] (EMEA). In October 2003, the FDA issued an ] for use of cilomilast in maintenance of lung function in COPD patients poorly responsive to salbutamol, despite an earlier decision by the FDA advisory panel to reject approval. The rejection was based on concerns over the efficacy of the agent, as well as gastrointestinal side effects.<ref>{{cite news|title=FDA Panel Rejects GSK's Ariflo|url=http://www.thepharmaletter.com/article/fda-panel-rejects-gsk-s-ariflo|access-date=3 October 2016|work=www.thepharmaletter.com|date=September 15, 2003}}</ref> Before issuing final approval, however, the FDA requested additional efficacy and safety data. The development of the drug was finally abandoned by GSK.<ref>{{cite book |editor1-last=Francis |editor1-first=Sharron H. |editor2-last=Conti |editor2-first=Marco |editor3-last=Houslay |editor3-first=Miles D. | name-list-style = vanc |title=Phosphodiesterases as drug targets |date=2011 |publisher=Springer-Verlag |location=Berlin, Heidelberg |isbn=978-3-642-17968-6 |page=89 }}</ref> |
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Cilomilast is a second-generation PDE4 inhibitor with ] effects that target ], ], and airway remodeling associated with COPD. |
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==Synthesis== |
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==Synthesis== |
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]<ref>{{cite journal | vauthors = Christensen SB, Guider A, Forster CJ, Gleason JG, Bender PE, Karpinski JM, DeWolf WE, Barnette MS, Underwood DC, Griswold DE, Cieslinski LB, Burman M, Bochnowicz S, Osborn RR, Manning CD, Grous M, Hillegas LM, Bartus JO, Ryan MD, Eggleston DS, Haltiwanger RC, Torphy TJ | display-authors = 6 | title = 1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma | journal = Journal of Medicinal Chemistry | volume = 41 | issue = 6 | pages = 821–35 | date = March 1998 | pmid = 9526558 | doi = 10.1021/jm970090r }}</ref> |
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== References == |
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{{Cite journal|doi=10.1021/jm970090r|title=1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma|pmid=9526558|year=1998|last1=Christensen|first1=Siegfried B.|last2=Guider|first2=Aimee|last3=Forster|first3=Cornelia J.|last4=Gleason|first4=John G.|last5=Bender|first5=Paul E.|last6=Karpinski|first6=Joseph M.|last7=Dewolf,|first7=Walter E.|last8=Barnette|first8=Mary S.|last9=Underwood|first9=David C.|journal=Journal of Medicinal Chemistry|volume=41|issue=6|pages=821}} |
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{{Reflist}} |
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==References== |
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<references/> |
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{{Phosphodiesterase inhibitors}} |
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{{Phosphodiesterase inhibitors}} |
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