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.
Highlights
Psoriasis is a common chronic inflammatory skin disease that affects 2% of the population.1 52.3% of patients were dissatisfied with current treatments in a recent survey from the National Psoriasis Foundation in the US.[1]
Sphingosine-1-phosphate receptor (S1PR) agonists are of interest to the pharmaceutical industry, due to their potential to treat diseases of the immune system such as psoriasis and multiple sclerosis as well as cancer.[5,6]
In 2010 fingolimod was approved for the treatment of relapsing/remitting multiple sclerosis and is the only S1PR1 agonist approved to date.[8]
Summary
Psoriasis is a common chronic inflammatory skin disease that affects 2% of the population.1 52.3% of patients were dissatisfied with current treatments in a recent survey from the National Psoriasis Foundation in the US.[1]. Due to the potential of S1PR agonists to act as efficacious therapies, for the treatment of psoriasis, we decided to embark on developing a topical S1PR1 modulator using a fast-follower approach, inspired by ponesimod. To select compounds which would be likely to demonstrate the desired pharmacokinetic profile, we targeted a human plasma stability half-life of < 5 min.
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