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.
Original language | English |
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Pages (from-to) | 3255-3259 |
Number of pages | 5 |
Journal | Bioorganic & Medicinal Chemistry Letters |
Volume | 28 |
Issue number | 19 |
Early online date | 30 Jul 2018 |
DOIs | |
Publication status | Published - 15 Oct 2018 |
Keywords
- Plasma stability
- Psoriasis
- S1PR1
- Soft-drug
- Topical
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry