Chemistry:Rubitecan
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| Trade names | Orathecin |
| Other names | 9-Nitrocamptothecin 9-NC 9-nitro-20(S)-camptothecin Camptogen (19S)-19-Ethyl-19-hydroxy-10-nitro-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaene-14,18-dione |
| Routes of administration | Oral (capsules) |
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| Pharmacokinetic data | |
| Bioavailability | 25–30% (rubitecan and 9-AC; in dogs) |
| Protein binding | 97% (rubitecan), 65% (9-AC) |
| Metabolism | Probably CYP-dependent |
| Metabolites | 9-Aminocamptothecin (9-AC) |
| Elimination half-life | 15–18 hours (rubitecan), 18–22 hours (9-AC) |
| Excretion | Bile and feces (major proportion), urine (the minor one)[1] |
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| Formula | C20H15N3O6 |
| Molar mass | 393.355 g·mol−1 |
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Rubitecan (INN, marketing name Orathecin) is an oral topoisomerase inhibitor, developed by SuperGen (now Astex Pharmaceuticals, Inc.; a member of the Otsuka Group).
History
On January 27, 2004, SuperGen announced that it has completed the submission of an NDA for rubitecan to the US FDA,[2] and was accepted for filing in March 2004.[3]
In January 2005, and under the direction of then-CEO James Manuso, SuperGen withdrew the NDA for rubitecan, based on feedback indicating that the current data package would not be sufficient to gain US approval,[4] and in January 2006, the Marketing Authorization Application (MAA) filed with the European Medicines Agency (EMA) was also withdrawn.[5]
The name Rubitecan is a portmanteau of SuperGen's founder, Dr. Joseph Rubinfeld, and the chemical name 9-Nitrocamptothecin.
Synthesis
Large scale production of Rubitecan has encountered problems. The direct nitration of camptothecin results in regioselectivity problems. One way that has been used to synthesize Rubitecan is to nitrate 10-hydroxycamptothecin then remove the hydroxyl functional group.[6]
Use as Anti-Cancer Drug
Rubitecan is a compound used extensively in cancer research. Rubitecan is an effective drug against pancreatic cancer and other solid tumors. One major problem is the lack of oral bioavailability due to low permeability and poor water solubility. One study shows 9-NC-SD through Soluplus1-based solid dispersion system is a much more effective delivery method than free 9-NC.[7]
References
- ↑ "Withdrawal Assessment Report for Orathecin (rubitecan). Applicant: EuroGen Pharmaceuticals, Ltd.". European Medicines Agency. 30 November 2007. pp. 4–8. http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/01/WC500069806.pdf.
- ↑ "SuperGen completes submission of New Drug Application (NDA) for Orathecin as an oral treatment for pancreatic cancer". Drugs.com. https://www.drugs.com/nda/orathecin_040128.html.
- ↑ "SuperGen's New Drug Application for Orathecin (rubitecan) capsules accepted by FDA for filing". Drugs.com. https://www.drugs.com/nda/orathecin_040326.html.
- ↑ "SuperGen Announces Withdrawal of Orathecin NDA". Drugs.com. https://www.drugs.com/nda/orathecin_050103.html.
- ↑ "Press release from the EMEA website regarding withdrawal of Orathecin MAA". http://www.emea.europa.eu/humandocs/PDFs/EPAR/orathecin/2621906en.pdf.
- ↑ "A Practical Regiospecific Synthesis of 9-Nitrocamptothecin". Synthesis 2006 (12): 1940–1942. 2006. doi:10.1055/s-2006-942359.
- ↑ "Soluplus(®) based 9-nitrocamptothecin solid dispersion for peroral administration: preparation, characterization, in vitro and in vivo evaluation". International Journal of Pharmaceutics 477 (1–2): 399–407. December 2014. doi:10.1016/j.ijpharm.2014.10.055. PMID 25445521.
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