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{{Short description|Chemical compound}}
{{Drugbox {{Drugbox
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 464383368 | verifiedrevid = 464383368
| IUPAC_name = (''RS'')-4-(3-cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-2-one | IUPAC_name = (''RS'')-4-(3-cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-2-one
| image = rolipram.svg | image = Rolipram.svg
| width = 200px | width = 200
| imagename = 1 : 1 mixture (racemate)
| drug_name = Rolipram


<!--Clinical data--> <!--Clinical data-->
| tradename = | tradename =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category = | pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S4 / S8 --> | legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| legal_UK = <!-- GSL / P / POM / CD --> | legal_UK = <!-- GSL / P / POM / CD -->
| legal_US = <!-- OTC / Rx-only --> | legal_US = <!-- OTC / Rx-only -->
| legal_status = | legal_status = Investigational
| routes_of_administration = | routes_of_administration =


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = 75%<ref name = PK>{{cite journal | vauthors = Krause W, Kühne G, Sauerbrey N | title = Pharmacokinetics of (+)-rolipram and (-)-rolipram in healthy volunteers | journal = European Journal of Clinical Pharmacology | volume = 38 | issue = 1 | pages = 71–75 | year = 1990 | pmid = 2328751 | doi = 10.1007/BF00314807 | s2cid = 25683209 }}</ref>
| bioavailability =
| protein_bound = | protein_bound =
| metabolism = ] via ], ], ] and ]<ref name = PK/>
| metabolism =
| elimination_half-life = 1-3 h | elimination_half-life = 3 hours<ref name = PK/>
| excretion = | excretion = Urine (80%)<ref name = PK/>


<!--Identifiers--> <!--Identifiers-->
| IUPHAR_ligand = 5260
| CASNo_Ref = {{cascite}}
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 61413-54-5 | CAS_number = 61413-54-5
| ATC_prefix = none | ATC_prefix = none
| ATC_suffix = | ATC_suffix =
| ATC_supplemental = | ATC_supplemental =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4913 | ChemSpiderID = 4913
Line 43: Line 43:
| PubChem = 5092 | PubChem = 5092
| DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = EXPT00228 | DrugBank = DB04149
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = K676NL63N7 | UNII = K676NL63N7
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 63 | ChEMBL = 63
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D01783


<!--Chemical data--> <!--Chemical data-->
| C=16 | H=21 | N=1 | O=3 | C=16 | H=21 | N=1 | O=3
| smiles = COc1ccc(cc1OC1CCCC1)C1CNC(=O)C1
| molecular_weight = 275.347 g/mol
}} }}


'''Rolipram''' is a selective ] discovered and developed by ] as a potential ] drug in the early 1990s.<ref name="Zhu 387–98">{{cite journal | vauthors = Zhu J, Mix E, Winblad B | title = The antidepressant and antiinflammatory effects of rolipram in the central nervous system | journal = CNS Drug Reviews | volume = 7 | issue = 4 | pages = 387–398 | date = Winter 2001 | pmid = 11830756 | pmc = 6741679 | doi = 10.1111/j.1527-3458.2001.tb00206.x }}</ref> It served as a prototype molecule for several companies' ] and development efforts.<ref name=McKenna>{{cite book | vauthors = McKenna JM, Muller GW | chapter = Chapter 33: Medicinal Chemistry of PDE4 Inhibitors. | title = Cyclic Nucleotide Phosphodiesterases in Health and Disease | veditors = Beavo J, Francis SH, Houslay MD | publisher = CRC Press | date = December 2006 | isbn = 9781420020847}}</ref>{{rp|668ff}} Rolipram was discontinued after clinical trials showed that its ] was too narrow; it could not be dosed at high enough levels to be effective without causing significant gastrointestinal side effects.<ref name=McKenna/>{{rp|668}}
'''Rolipram''' is a ]. Like most PDE4-inhibitors, it is an anti-inflammatory drug.<ref name="Anti-inflammatory-Griswold">{{cite journal | author=Griswold DE, Webb EF, Breton J, White JR, Marshall PJ, Torphy TJ. | title=Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response | journal=Inflammation | year=1993 | pages=333–44 | volume=17 | issue=3 | pmid=7687237 | doi=10.1007/BF00918994}}</ref> Rolipram is being studied as a possible alternative to current ].<ref name="Antidepressant-Bobon">{{cite journal | author=Bobon D, Breulet M, Gerard-Vandenhove MA, Guiot-Goffioul F, Plomteux G, Sastre-y-Hernandez M, Schratzer M, Troisfontaines B, von Frenckell R, Wachtel H. | title=Is phosphodiesterase inhibition a new mechanism of antidepressant action? A double blind double-dummy study between rolipram and desipramine in hospitalized major and/or endogenous depressives | journal=Eur Arch Psychiatry Neurol Sci | year=1988 | pages=2–6 | volume=238 | issue=1 | pmid=3063534}}</ref><ref name="Potential-antidepressant-Wachtel">{{cite journal | author=Wachtel H. | title=Potential antidepressant activity of rolipram and other selective cyclic adenosine 3',5'-monophosphate phosphodiesterase inhibitors | journal=Neuropharmacology | year=1983 | pages=267–72 | volume=22 | issue=3 | pmid=6302550 | doi=10.1016/0028-3908(83)90239-3}}</ref> Recent studies show that rolipram may have ] effects.<ref name="Antipsychotic-Maxwell">{{cite journal | author=Maxwell CR, Kanes SJ, Abel T, Siegel SJ. | title=Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications | journal=Neuroscience | year=2004 | pages=101–7 | volume=129 | issue=1 | pmid=15489033 | doi=10.1016/j.neuroscience.2004.07.038}}</ref><ref name="Antipsychotic-Kanes">{{cite journal | author=Kanes SJ, Tokarczyk J, Siegel SJ, Bilker W, Abel T, Kelly MP. | title=Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity | journal=Neuroscience | year=2006 | pages= 239–46| volume= 144| issue= 1| pmid=17081698 | doi=10.1016/j.neuroscience.2006.09.026}}</ref> Other beneficial effects of rolipram are:
* Improved long term memory<ref name="LTP-Barad">{{cite journal | author=Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E. | title=Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory | journal=Proceedings of the National Academy of Science of the USA. | year=1998 | pages=15020–5 | volume=95 | issue=25 | pmid=9844008 | doi=10.1073/pnas.95.25.15020 | pmc=24568}}</ref>
* Increased wakefulness<ref name="Wakefulness-Lelkes">{{cite journal | author=Lelkes Z, Alföldi P, Erdos A, Benedek G. | title=Rolipram, an antidepressant that increases the availability of cAMP, transiently enhances wakefulness in rats | journal=Pharmacology, Biochemistry and Behaviour | year=1998 | pages=835–9 | volume=60 | issue=4 | pmid=9700966 | doi=10.1016/S0091-3057(98)00038-0}}</ref>
* Increased ]<ref name="Rolipram-Neuroprotection-Block">{{cite journal | author=Block F, Schmidt W, Nolden-Koch M, Schwarz M. | title=Rolipram reduces excitotoxic neuronal damage | journal=Neuroreport | year=2001 | pages=1507–11 | volume=12 | issue=7 | pmid=11388438 | doi=10.1097/00001756-200105250-00041}}</ref><ref name="PDEIs-Neuroprotection-Chen">{{cite journal | author=Chen RW, Williams AJ, Liao Z, Yao C, Tortella FC, Dave JR. | title=Broad spectrum neuroprotection profile of phosphodiesterase inhibitors as related to modulation of cell-cycle elements and caspase-3 activation | journal=Neuroscience Letters | year=2007 | pages=165–9 | volume=418 | issue=2 | pmid=17398001 | doi=10.1016/j.neulet.2007.03.033}}</ref>
Rolipram shows promise in ameliorating ],<ref name='PNAS 2009-9-14'>{{cite journal|title=Reversal of long-term dendritic spine alterations in Alzheimer disease models|journal=Proceedings of the National Academy of Sciences of the United States | date=September 14, 2009 | first=Donna L|last= Smith|coauthors=Pozueta J, Gong B, Arancio O, Shelanski M | volume=106 | issue=39 | pages=16877–16882 | pmid= 19805389 | doi = 10.1073/pnas.0908706106 | url=http://www.pnas.org/content/106/39/16877.full|format=|accessdate=2009-11-13|pmc=2743726 }}</ref> ] <ref name='U. S. ARMY MEDICAL RESEARCH 2005 1-1'>{{cite web|url=http://handle.dtic.mil/100.2/ADA434051 |title=Oxidative Damage in Parkinson's Disease |accessdate=2009-11-13 |last=MF |first=Beal |coauthors=Cleren C, Calingasan NY, Yang L, Klivenyi P, Lorenzl S |year=2005 |publisher=U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012 }}</ref> and also in the regeneration of severed spinal cord axonal bodies.<ref name='NCBI PUB/MED.GOV Jun. 8, 2004'> {{cite journal|last1=Nikulina|first1=E.|title=The Phosphodiesterase Inhibitor Rolipram Delivered after a Spinal Cord Lesion Promotes Axonal Regeneration and Functional Recovery|journal=Proceedings of the National Academy of Sciences of the United States|volume=101|pages=8786|date=June 8, 2004 |doi=10.1073/pnas.0402595101 | jstor=3372336 }}</ref>


Rolipram has several activities that make it a continuing focus for research. The etiology of many ] involves misfolded and clumped proteins which accumulate in the brain. Cells have a mechanism to dispose of such proteins called the ]. However, in ] and some other conditions the activity of these proteasomes is impaired leading to a buildup of toxic aggregates. Research in mice suggests that rolipram has the ability to ramp up the activity of proteasomes and reduce the burden of these aggregates. Preliminary evidence suggests that this can improve spatial memory in mice engineered to have aggregate build-up.<ref name="Myeku 46-53">{{cite journal | vauthors = Myeku N, Clelland CL, Emrani S, Kukushkin NV, Yu WH, Goldberg AL, Duff KE | title = Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling | journal = Nature Medicine | volume = 22 | issue = 1 | pages = 46–53 | date = January 2016 | pmid = 26692334 | pmc = 4787271 | doi = 10.1038/nm.4011 }}</ref> Rolipram continues to be used in research as a well-characterized PDE4 inhibitor.<ref name=McKenna/>{{rp|669}} It has been used in studies to understand whether PDE4 inhibition could be useful in ],<ref>{{cite journal | vauthors = Kumar N, Goldminz AM, Kim N, Gottlieb AB | title = Phosphodiesterase 4-targeted treatments for autoimmune diseases | journal = BMC Medicine | volume = 11 | issue = 1 | pages = 96 | date = April 2013 | pmid = 23557064 | pmc = 3616808 | doi = 10.1186/1741-7015-11-96 | doi-access = free }}</ref> Alzheimer's disease,<ref>{{cite journal | vauthors = García-Osta A, Cuadrado-Tejedor M, García-Barroso C, Oyarzábal J, Franco R | title = Phosphodiesterases as therapeutic targets for Alzheimer's disease | journal = ACS Chemical Neuroscience | volume = 3 | issue = 11 | pages = 832–844 | date = November 2012 | pmid = 23173065 | pmc = 3503343 | doi = 10.1021/cn3000907 }}</ref> cognitive enhancement,<ref>{{cite journal | vauthors = Normann C, Berger M | title = Neuroenhancement: status quo and perspectives | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 258 | issue = Suppl 5 | pages = 110–114 | date = November 2008 | pmid = 18985306 | doi = 10.1007/s00406-008-5022-2 | s2cid = 9733191 }}</ref> spinal cord injury,<ref>{{cite journal | vauthors = Hannila SS, Filbin MT | title = The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury | journal = Experimental Neurology | volume = 209 | issue = 2 | pages = 321–332 | date = February 2008 | pmid = 17720160 | pmc = 2692909 | doi = 10.1016/j.expneurol.2007.06.020 }}</ref> and respiratory diseases like ] and ].<ref>{{cite journal | vauthors = Huang Z, Mancini JA | title = Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD | journal = Current Medicinal Chemistry | volume = 13 | issue = 27 | pages = 3253–3262 | year = 2006 | pmid = 17168849 | doi = 10.2174/092986706778773040 }}</ref>
==See also==
*]s


==References== == See also ==
*]
⚫ {{Reflist}}

== References ==
⚫ {{Reflist|33em}}


{{Phosphodiesterase inhibitors}} {{Phosphodiesterase inhibitors}}


] ]
⚫ ]
] ]
⚫ ]

]
]
]
]

Latest revision as of 18:38, 8 December 2023

Chemical compound Pharmaceutical compound
Rolipram
Clinical data
ATC code
  • none
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Bioavailability75%
MetabolismLiver via CYP2C8, CYP2C9, CYP2C19 and CYP2D6
Elimination half-life3 hours
ExcretionUrine (80%)
Identifiers
IUPAC name
  • (RS)-4-(3-cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.057.046 Edit this at Wikidata
Chemical and physical data
FormulaC16H21NO3
Molar mass275.348 g·mol
3D model (JSmol)
SMILES
  • COc1ccc(cc1OC1CCCC1)C1CNC(=O)C1
InChI
  • InChI=1S/C16H21NO3/c1-19-14-7-6-11(12-9-16(18)17-10-12)8-15(14)20-13-4-2-3-5-13/h6-8,12-13H,2-5,9-10H2,1H3,(H,17,18)
  • Key:HJORMJIFDVBMOB-UHFFFAOYSA-N
  (what is this?)  (verify)

Rolipram is a selective phosphodiesterase-4 inhibitor discovered and developed by Schering AG as a potential antidepressant drug in the early 1990s. It served as a prototype molecule for several companies' drug discovery and development efforts. Rolipram was discontinued after clinical trials showed that its therapeutic window was too narrow; it could not be dosed at high enough levels to be effective without causing significant gastrointestinal side effects.

Rolipram has several activities that make it a continuing focus for research. The etiology of many neurodegenerative diseases involves misfolded and clumped proteins which accumulate in the brain. Cells have a mechanism to dispose of such proteins called the proteasome. However, in Alzheimer's disease and some other conditions the activity of these proteasomes is impaired leading to a buildup of toxic aggregates. Research in mice suggests that rolipram has the ability to ramp up the activity of proteasomes and reduce the burden of these aggregates. Preliminary evidence suggests that this can improve spatial memory in mice engineered to have aggregate build-up. Rolipram continues to be used in research as a well-characterized PDE4 inhibitor. It has been used in studies to understand whether PDE4 inhibition could be useful in autoimmune diseases, Alzheimer's disease, cognitive enhancement, spinal cord injury, and respiratory diseases like asthma and COPD.

See also

References

  1. ^ Krause W, Kühne G, Sauerbrey N (1990). "Pharmacokinetics of (+)-rolipram and (-)-rolipram in healthy volunteers". European Journal of Clinical Pharmacology. 38 (1): 71–75. doi:10.1007/BF00314807. PMID 2328751. S2CID 25683209.
  2. Zhu J, Mix E, Winblad B (Winter 2001). "The antidepressant and antiinflammatory effects of rolipram in the central nervous system". CNS Drug Reviews. 7 (4): 387–398. doi:10.1111/j.1527-3458.2001.tb00206.x. PMC 6741679. PMID 11830756.
  3. ^ McKenna JM, Muller GW (December 2006). "Chapter 33: Medicinal Chemistry of PDE4 Inhibitors.". In Beavo J, Francis SH, Houslay MD (eds.). Cyclic Nucleotide Phosphodiesterases in Health and Disease. CRC Press. ISBN 9781420020847.
  4. Myeku N, Clelland CL, Emrani S, Kukushkin NV, Yu WH, Goldberg AL, Duff KE (January 2016). "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling". Nature Medicine. 22 (1): 46–53. doi:10.1038/nm.4011. PMC 4787271. PMID 26692334.
  5. Kumar N, Goldminz AM, Kim N, Gottlieb AB (April 2013). "Phosphodiesterase 4-targeted treatments for autoimmune diseases". BMC Medicine. 11 (1): 96. doi:10.1186/1741-7015-11-96. PMC 3616808. PMID 23557064.
  6. García-Osta A, Cuadrado-Tejedor M, García-Barroso C, Oyarzábal J, Franco R (November 2012). "Phosphodiesterases as therapeutic targets for Alzheimer's disease". ACS Chemical Neuroscience. 3 (11): 832–844. doi:10.1021/cn3000907. PMC 3503343. PMID 23173065.
  7. Normann C, Berger M (November 2008). "Neuroenhancement: status quo and perspectives". European Archives of Psychiatry and Clinical Neuroscience. 258 (Suppl 5): 110–114. doi:10.1007/s00406-008-5022-2. PMID 18985306. S2CID 9733191.
  8. Hannila SS, Filbin MT (February 2008). "The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury". Experimental Neurology. 209 (2): 321–332. doi:10.1016/j.expneurol.2007.06.020. PMC 2692909. PMID 17720160.
  9. Huang Z, Mancini JA (2006). "Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD". Current Medicinal Chemistry. 13 (27): 3253–3262. doi:10.2174/092986706778773040. PMID 17168849.
Phosphodiesterase inhibitors
PDE1
PDE2
PDE3
PDE4
PDE5
PDE7
PDE9
PDE10
PDE11BC11-38
Non-selective
Unsorted
See also: Receptor/signaling modulators
Categories: