期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 19, 页码 3255-3259出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.07.044
关键词
S1PR1; Soft-drug; Plasma stability; Psoriasis; Topical
资金
- Wellcome Trust Strategic Award [098439/Z/12/Z]
- Wellcome Trust [098439/Z/12/Z] Funding Source: Wellcome Trust
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.
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