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

Mark Bell; David Foley; Claire Naylor; Colin Robinson; Jennifer Riley; Rafiu Epemolu; Stanley Scullion; Yoko Shishikura; Elad Katz; William McLean; Paul Wyatt; Kevin Read; Christopher Woodland

doi:10.1016/j.bmcl.2018.07.044

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

Mark Bell (Lead / Corresponding author), David Foley, Claire Naylor, Colin Robinson, Jennifer Riley, Rafiu Epemolu, Stanley Scullion, Yoko Shishikura, Elad Katz, William McLean, Paul Wyatt, Kevin Read, Christopher Woodland (Lead / Corresponding author)

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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
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	https://doi.org/10.1016/j.bmcl.2018.07.044
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

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10.1016/j.bmcl.2018.07.044Licence: CC BY

Author Accepted Manuscript
© 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Accepted author manuscript, 862 KBLicence: CC BY-NC-ND
Publisher final version
0960-894X/ © 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).
Final published version, 462 KBLicence: CC BY

Cite this

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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.",

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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). ",

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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

SN - 0960-894X

VL - 28

SP - 3255

EP - 3259

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 19

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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