The sphingosine 1-‐phosphate receptor modulator fingolimod / Gilenya / FTY720 has become an effective and commercially available therapeutic agent for the treatment of relapsing-‐remitting multiple sclerosis. Fingolimod is phosphorylated by sphingosine kinase in vivo to the pharmacologically active S-‐fingolimod phosphate. The original aim of the work was to synthesise novel phosphate delivery prodrug analogues of fingolimod and determine whether or not these novel analogues could provide an improved therapeutic profile. The principal phosphate delivery prodrug method to be investigated was phosphoramidate “ProTide” chemistry. ProTide fingolimod analogues were found to have a poor level of stability and readily degrade to unwanted cyclised structures at room temperature and when exposed to very mildly basic conditions. In order to mitigate the poor stability issues it was considered possible that forming ProTide analogues of mono-‐alcohol S1P receptor modulators, as opposed to diol fingolimod, would lead to greater stability. The synthesis of mono-‐alcohol S1P receptor modulator benzyl ether derivative analogues published by Tsuji et al was attempted and successfully achieved. Previously reported ProTide synthesis and in vitro testing methods were employed. Carboxypeptidase, human serum, base stability, acid stability and cell lysate processing experiments were conducted in the School of Pharmacy. Homology modelling was employed to determine S1P1 selectivity of benzyl ether derivative analogues and novel structures. ProTide benzyl ether derivative analogues were found to have a far greater level of stability than ProTide fingolimod analogues and in vitro processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research signifies the development of an entirely new family of potential therapeutic agents.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:704959 |
| Date | January 2017 |
| Creators | James, Edward |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/98066/ |
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