[HTML][HTML] Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1
M Bell, D Foley, C Naylor, C Robinson, J Riley… - Bioorganic & Medicinal …, 2018 - Elsevier
Bioorganic & Medicinal Chemistry Letters, 2018•Elsevier
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 …
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 …
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.
Elsevier