Rolipram

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Rolipram
Rolipram2DACS.svg
Rolipram3Dan2.gif
Systematic (IUPAC) name
(RS)-4-(3-cyclopentyloxy-4-methoxy-phenyl)pyrrolidin-2-one
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Bioavailability 75%[1]
Metabolism Hepatic via CYP2C8, CYP2C9, CYP2C19 and CYP2D6[1]
Biological half-life 3 hours[1]
Excretion Urine (80%)[1]
Identifiers
CAS Number 61413-54-5 YesY
ATC code none
PubChem CID 5092
IUPHAR/BPS 5260
DrugBank DB04149 N
ChemSpider 4913 YesY
UNII K676NL63N7 YesY
ChEBI CHEBI:104872 YesY
ChEMBL CHEMBL63 YesY
Chemical data
Formula C16H21NO3
Molar mass 275.347 g/mol
 NYesY (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] It 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[edit]

  1. ^ a b c d Krause, W; Kühne, G; Sauerbrey, N (1990). "Pharmacokinetics of (+)-rolipram and (−)-rolipram in healthy volunteers" (PDF). European Journal of Clinical Pharmacology 38 (1): 71–75. doi:10.1007/BF00314807. PMID 2328751. 
  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): 387–98. doi:10.1111/j.1527-3458.2001.tb00206.x. PMID 11830756. 
  3. ^ a b c McKenna, JM and Muller, GW. Medicinal Chemistry of PDE4 Inhibitors. Chapter 33 in Cyclic Nucleotide Phosphodiesterases in Health and Disease, Eds Joseph A. Beavo et al. CRC Press, Dec 5, 2006 ISBN 9781420020847
  4. ^ Myeku, Natura (December 21, 2015). "Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.". Nature Medicine. doi:10.1038/nm.4011. 
  5. ^ Kumar N, et al. (Apr 2013). "Phosphodiesterase 4-targeted treatments for autoimmune diseases". BMC Med. 11 (1): 96. doi:10.1186/1741-7015-11-96. PMID 23557064. 
  6. ^ García-Osta A, et al. (Nov 2012). "Phosphodiesterases as therapeutic targets for Alzheimer's disease". ACS Chem Neurosci 3 (11): 832–44. doi:10.1021/cn3000907. PMID 23173065. 
  7. ^ Normann C, Berger M (Nov 2008). "Neuroenhancement: status quo and perspectives". Eur Arch Psychiatry Clin Neurosci 258 (Suppl 5): 110–4. doi:10.1007/s00406-008-5022-2. PMID 18985306. 
  8. ^ Hannila SS, Filbin MT (Feb 2008). "The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury". Exp Neurol 209 (2): 321–32. doi:10.1016/j.expneurol.2007.06.020. PMID 17720160. 
  9. ^ Huang Z, Mancini JA (2006). "Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD". Curr Med Chem. 13 (27): 3253–62. doi:10.2174/092986706778773040. PMID 17168849.