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Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1
Authors:Mark Bell  David Foley  Claire Naylor  Colin Robinson  Jennifer Riley  Ola Epemolu  Paul Scullion  Yoko Shishikura  Elad Katz  W.H. Irwin McLean  Paul Wyatt  Kevin D. Read  Andrew Woodland
Affiliation:1. The Drug Discovery Unit, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 4HN, UK;2. Dermatology and Genetic Medicine, Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK
Abstract:
The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.
Keywords:S1PR1  Soft-drug  Plasma stability  Psoriasis  Topical
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