Tissue distribution, pharmacokinetics and identification of roscovitine metabolites in rat

Vita, Marina; Abdel‐Rehim, Mohamed; Olofsson, S.; Hassan, Zuzana; Meurling, Lennart; Sidén, Å; Sidén, Mabel; Pettersson, Tommy; Hassan, Moustapha

doi:10.1016/j.ejps.2005.02.001

Cited by 54 publications

(58 citation statements)

References 18 publications

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“…116,117 In contrast, roscovitine has been described to penetrate the BBB at a sufficient rate. 118 GSK3. The GSK-3 isoforms ␣ and ␤ are encoded by two different genes.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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“…116,117 In contrast, roscovitine has been described to penetrate the BBB at a sufficient rate. 118 GSK3. The GSK-3 isoforms ␣ and ␤ are encoded by two different genes.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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“…It is a carboxylated form of roscovitine, while the second metabolite is the glucuronide form of metabolite one. No metabolites were detected in the brain (Figure 8) [131,132]. High protein binding of roscovitine (92% to 96%) was shown in human and mouse plasma [124,133].…”

mentioning

confidence: 97%

“…In vitro and in vivo metabolism of roscovitine was reported recently [131,135,138,139]. Several metabolites were identified, including the carboxylate metabolite (oxidation of the alcohol group at C2 of the purine ring) [131].…”

mentioning

confidence: 99%

“…Several metabolites were identified, including the carboxylate metabolite (oxidation of the alcohol group at C2 of the purine ring) [131]. Cytochrome P450, mainly CYP3A4 and CYP2B6 enzymes, has been shown to metabolize roscovitine.…”

mentioning

confidence: 99%

“…Vita et al [131] described roscovitine PK in rat as a two-compartment open model with a short elimination half-life of <30 min (Table 5). The distribution of roscovitine was highest in the lungs, followed by liver, fat, and kidney, while exposure to roscovitine in the brain was 30% of that observed in plasma ( Figure 6).…”

mentioning

confidence: 99%

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From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

Zhelev

Trifonov²,

Wang³

et al. 2013

Biodiscovery

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This monograph reviews the discovery and development of the cyclindependent kinase inhibitor roscovitine (R-roscovitine, CYC202, Seliciclib). The authors summarise the in vitro and in vivo data that have formed the basis for clinical investigation of Seliciclib as an anti-cancer drug. Kinase selectivity, cellular effects and the pharmacological properties of the drug are discussed in addition to the clinical results of Seliciclib being reviewed. Novel results on the effect of the drug in cardiac hypertrophy are summarized and potential applications of Seliciclib in other therapeutic areas, including, inflammation, virology, glomerulonephritis and polycystic kidney disease, are discussed. Finally the authors argue that optimisation of the therapeutic effect of kinase inhibitors such as Seliciclib can be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division. Seliciclib -discovery and developmentBioDiscovery 2 December 2013 | Issue 10 | 1

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High Performance Liquid Chromatography‐Electrochemistry‐Electrospray Ionization Mass Spectrometry (HPLC/EC/ESI‐MS) for Detection and Characterization of Roscovitine Oxidation Products

Karády¹,

Novák²,

Horna³

et al. 2011

Electroanalysis

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On-line LC-EC/ESI-MS has been established as a fast and simple method to mimic some types of oxidation reaction of various drugs and to study the formation and structure of the resulting products. This technique has been applied to a 2,6,9-trisubstituted purine, R-roscovitine, which is known to be an inhibitor of some cyclin-dependent kinases (CDKs) and a potential anticancer drug. Oxidation of R-roscovitine in an electrochemical cell (EC), operated under various conditions, resulted in appearance of 6 major products. These were further analyzed by high-resolution mass spectrometry, their structures were elucidated by accurate mass measurement and compared to previously identified R-roscovitine in vitro/in vivo metabolites. Although none of the observed products was structurally identical to those identified previously in vitro/in vivo, all of them, except for the methoxylated products, resembled similarity due to appearing through the same reaction type. R-roscovitine in the EC cell underwent N-dealkylation of the isopropyl moiety, hydroxylation of the aromatic side-chain, dihydroxylation, methoxylation and dimer formation. The hydroxylation product was identified as Olomoucine II, a R-roscovitine derivative, which displays 10-times higher CDK-inhibiting activity than R-roscovitine and the occurrence of which, as R-roscovitine product, has not yet been observed in vitro/in vivo.

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Tissue distribution, pharmacokinetics and identification of roscovitine metabolites in rat

Cited by 54 publications

References 18 publications

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Tau-Based Treatment Strategies in Neurodegenerative Diseases

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

High Performance Liquid Chromatography‐Electrochemistry‐Electrospray Ionization Mass Spectrometry (HPLC/EC/ESI‐MS) for Detection and Characterization of Roscovitine Oxidation Products

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