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Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1

Bell, Mark, Foley, David, Naylor, Claire, Robinson, Colin, Riley, Jennifer, Epemolu, Ola, Scullion, Paul, Shishikura, Yoko, Katz, Elad, McLean, W. H. Irwin, Wyatt, Paul, Read, Kevin D. and Woodland, Andrew 2018. Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1. Bioorganic & Medicinal Chemistry Letters 28 (19) , pp. 3255-3259. 10.1016/j.bmcl.2018.07.044

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier
ISSN: 0960-894X
Date of First Compliant Deposit: 31 July 2018
Date of Acceptance: 29 July 2018
Last Modified: 11 Oct 2018 09:33

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