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Rolipram - Wikipedia

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Rolipram
Clinical data

ATC code	none
Legal status
Legal status	Investigational
Pharmacokinetic data
Bioavailability	75%^[1]
Metabolism	Liver via CYP2C8, CYP2C9, CYP2C19 and CYP2D6^[1]
Elimination half-life	3 hours^[1]
Excretion	Urine (80%)^[1]
Identifiers
IUPAC name (RS)-4-(3-cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-2-one
CAS Number	61413-54-5^Y
PubChem CID	5092
IUPHAR/BPS	5260
DrugBank	DB04149^N
ChemSpider	4913^Y
UNII	K676NL63N7
KEGG	D01783^N
ChEBI	CHEBI:104872^Y
ChEMBL	ChEMBL63^Y
CompTox Dashboard (EPA)	DTXSID3044124
ECHA InfoCard	100.057.046
Chemical and physical data
Formula	C₁₆H₂₁NO₃
Molar mass	275.348 g·mol⁻¹
3D model (JSmol)	Interactive image
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)^Y Key:HJORMJIFDVBMOB-UHFFFAOYSA-N^Y
^NY (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.^[2] It served as a prototype molecule for several companies' drug discovery and development efforts.^[3]^: 668ff 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.^[3]^: 668

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.^[4] Rolipram continues to be used in research as a well-characterized PDE4 inhibitor.^[3]^: 669 It has been used in studies to understand whether PDE4 inhibition could be useful in autoimmune diseases,^[5] Alzheimer's disease,^[6] cognitive enhancement,^[7] spinal cord injury,^[8] and respiratory diseases like asthma and COPD.^[9]

References

^ ^a ^b ^c ^d 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.
^ 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.
^ ^a ^b ^c 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.

v t e Phosphodiesterase inhibitors
PDE1	MMPX SCH-51866 Vinpocetine
PDE2	BAY 60-7550 Carbazeran EHNA Oxindole PDP
PDE3	Adibendan Amrinone (inamrinone) Anagrelide Benafentrine Bucladesine Carbazeran Cilostamide Cilostazol Enoximone Ensifentrine Imazodan KMUP-1 Meribendan Milrinone Olprinone Parogrelil Pimobendan Pumafentrine Quazinone RPL-554 Siguazodan Trequinsin Vesnarinone Zardaverine
PDE4	Apremilast Arofylline Atizoram Benafentrine Catramilast CC-1088 CDP-840 CGH-2466 Cilomilast Cipamfylline Crisaborole Denbutylline Difamilast Drotaverine Ensifentrine Etazolate Filaminast Glaucine HT-0712 ICI-63197 Indimilast Irsogladine Lavamilast Lirimilast Lotamilast Luteolin Mesembrenone Mesembrine Mesopram Oglemilast Piclamilast Pumafentrine Revamilast Ro 20-1724 Roflumilast Rolipram Ronomilast RPL-554 RS-25344 Tetomilast Tofimilast YM-976 Zardaverine
PDE5	Acetildenafil Aildenafil Avanafil Beminafil Benzamidenafil Dasantafil Icariin Gisadenafil Homosildenafil Lodenafil Mirodenafil MY-5445 Nitrosoprodenafil Norcarbodenafil SCH-51866 Sildenafil Sulfoaildenafil T-0156 Tadalafil Udenafil Vardenafil
PDE7	BRL-50481
PDE9	BAY 73-6691 PF-04447943 Paraxanthine
PDE10	Balipodect Mardepodect MK-8189 Papaverine TC-E 5005 Tofisopam
PDE11	BC11-38
Non-selective	Aminophylline Caffeine Choline theophyllinate CPX Dipyridamole Doxofylline Enprofylline Ibudilast IBMX Luteolin Pentoxifylline Propentofylline Theobromine Theophylline Zaprinast
Unsorted	Diazepam Diprophylline DPCPX Furafylline Lisofylline MDL-12330A Moxaverine Oxagrelate Pentifylline Proxyphylline Quercetin Satigrel Tolafentrine Trapidil
See also: Receptor/signaling modulators

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