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

Research output: Contribution to journalArticle

3 Citations (Scopus)
121 Downloads (Pure)

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 languageEnglish
Pages (from-to)3255-3259
Number of pages5
JournalBioorganic & Medicinal Chemistry Letters
Volume28
Issue number19
Early online date30 Jul 2018
DOIs
Publication statusPublished - 15 Oct 2018

Fingerprint

Lysosphingolipid Receptors
Modulators
Esters
Plasma (human)
Butyrylcholinesterase
Aryldialkylphosphatase
Phase II Clinical Trials
Plasma stability
Lymphopenia
Esterases
Bradycardia
Psoriasis
Pharmaceutical Preparations
Plasmas
Substrates
ponesimod
Therapeutics

Keywords

  • Plasma stability
  • Psoriasis
  • S1PR1
  • Soft-drug
  • Topical

Cite this

@article{4411ff61b3f64d898c2f74685b5fcf1e,
title = "Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1",
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.",
keywords = "Plasma stability, Psoriasis, S1PR1, Soft-drug, Topical",
author = "Mark Bell and David Foley and Claire Naylor and Colin Robinson and Jennifer Riley and Rafiu Epemolu and Stanley Scullion and Yoko Shishikura and Elad Katz and William McLean and Paul Wyatt and Kevin Read and Christopher Woodland",
note = "The Centre for Dermatology and Genetic Medicine is supported by a Wellcome Trust Strategic Award (reference 098439/Z/12/Z).",
year = "2018",
month = "10",
day = "15",
doi = "10.1016/j.bmcl.2018.07.044",
language = "English",
volume = "28",
pages = "3255--3259",
journal = "Bioorganic & Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier",
number = "19",

}

TY - JOUR

T1 - Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1

AU - Bell, Mark

AU - Foley, David

AU - Naylor, Claire

AU - Robinson, Colin

AU - Riley, Jennifer

AU - Epemolu, Rafiu

AU - Scullion, Stanley

AU - Shishikura, Yoko

AU - Katz, Elad

AU - McLean, William

AU - Wyatt, Paul

AU - Read, Kevin

AU - Woodland, Christopher

N1 - The Centre for Dermatology and Genetic Medicine is supported by a Wellcome Trust Strategic Award (reference 098439/Z/12/Z).

PY - 2018/10/15

Y1 - 2018/10/15

N2 - 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.

AB - 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.

KW - Plasma stability

KW - Psoriasis

KW - S1PR1

KW - Soft-drug

KW - Topical

U2 - 10.1016/j.bmcl.2018.07.044

DO - 10.1016/j.bmcl.2018.07.044

M3 - Article

C2 - 30143424

VL - 28

SP - 3255

EP - 3259

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

SN - 0960-894X

IS - 19

ER -