title: Kinase-independent phosphoramidate S1P1receptor agonist benzyl ether derivatives.
abstract: Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P1-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators. Carboxypeptidase, human serum and cell lysate processing experiments were conducted. ProTide BED analogues were found to have an acceptable level of stability in acidic and basic conditions and in vitro metabolic processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research describes the development of an entirely novel family of therapeutic agents.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. Electronic address: edward.james.correspondence@hotmail.com.
authors.forename: Edward
authors.initials: E
authors.lastname: James
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pertusati
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: McGuigan
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D010756:Phosphoric Acids / Q000494:pharmacology*; D010770:Phosphotransferases / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000819:agonists*
chemical_list: D000577:Amides; D010756:Phosphoric Acids; D049349:Receptors, Lysosphingolipid; C011067:phosphoramidic acid; D010770:Phosphotransferases
keywords: Benzyl ether derivative; Enzymatic processing; Phosphoramidate; ProTide; S1P(1) receptor agonist; Sphingosine kinase