Kinase-independent phosphoramidate S1P1 receptor agonist benzyl ether derivatives

James, Edward, Pertusati, Fabrizio ORCID: https://orcid.org/0000-0003-4532-9101, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419 and McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X 2017. Kinase-independent phosphoramidate S1P1 receptor agonist benzyl ether derivatives. Biorganic and Medicinal Chemistry Letters 27 (6) , pp. 1371-1378. 10.1016/j.bmcl.2017.02.011

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Subjects:	R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords:	S1P1 receptor agonist; Benzyl ether derivative; Phosphoramidate; ProTide; Sphingosine kinase; Enzymatic processing
Publisher:	Elsevier
ISSN:	0960-894X
Date of First Compliant Deposit:	23 February 2017
Date of Acceptance:	5 February 2017
Last Modified:	18 Nov 2024 00:15
URI:	https://orca.cardiff.ac.uk/id/eprint/98504

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