2. Academic Validation
  3. Discovery of Soft-Drug Topical Tool Modulators of Sphingosine-1-phosphate Receptor 1 (S1PR1)

Discovery of Soft-Drug Topical Tool Modulators of Sphingosine-1-phosphate Receptor 1 (S1PR1)

  • ACS Med Chem Lett. 2019 Feb 14;10(3):341-347. doi: 10.1021/acsmedchemlett.8b00616.
Mark Bell 1,  David Foley 2,  Claire Naylor 1,  Gavin Wood 1,  Colin Robinson 1,  Jennifer Riley 1,  Ola Epemolu 1,  Lucy Ellis 3,  Paul Scullion 1,  Yoko Shishikura 1,  Maria Osuna-Cabello 1,  Liam Ferguson 1,  Erika Pinto 1,  Daniel Fletcher 1,  Elad Katz 1,  W H Irwin McLean 4,  Paul Wyatt 1,  Kevin D Read 1,  Andrew Woodland 1
Affiliations

Affiliations

  • 1 Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DDI 5EH, U.K.
  • 2 Medicines Discovery Institute, Cardiff University, Cardiff CF10 3XQ, U.K.
  • 3 New Modalities, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 4 Dermatology and Genetic Medicine, Division of Molecular Medicine, University of Dundee, Dundee DD1 5EH, U.K.
PMID: 30891137 DOI: 10.1021/acsmedchemlett.8b00616
Abstract

In order to study the role of S1PRs in inflammatory skin disease, S1PR modulators are dosed orally and topically in animal models of disease. The topical application of S1PR modulators in these models may, however, lead to systemic drug concentrations, which can complicate interpretation of the observed effects. We set out to design soft drug S1PR modulators as topical tool compounds to overcome this limitation. A fast follower approach starting from the drug ponesimod allowed the rapid development of an active phenolic series of soft drugs. The Phenols were, however, chemically unstable. Protecting the phenol as an ester removed the instability and provided a compound that is converted by enzymatic hydrolysis in the skin to the phenolic soft drug species. In simple formulations, topical dosing of these S1PR modulators to mice led to micromolar skin concentrations but no detectable blood concentrations. These topical tools will allow researchers to investigate the role of S1PR in skin, without involvement of systemic S1PR biology.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z