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

被引：7

作者：

Bell, Mark ^{[1
]}

Foley, David ^{[2
]}

Naylor, Claire ^{[1
]}

Wood, Gavin ^{[1
]}

Robinson, Colin ^{[1
]}

Riley, Jennifer ^{[1
]}

Epemolu, Ola ^{[1
]}

Ellis, Lucy ^{[3
]}

Scullion, Paul ^{[1
]}

Shishikura, Yoko ^{[1
]}

Osuna-Cabello, Maria ^{[1
]}

Ferguson, Liam ^{[1
]}

Pinto, Erika ^{[1
]}

Fletcher, Daniel ^{[1
]}

Katz, Elad ^{[1
]}

McLean, W. H. Irwin ^{[4
]}

Wyatt, Paul ^{[1
]}

Read, Kevin D. ^{[1
]}

Woodland, Andrew ^{[1
]}

机构：

[1] Univ Dundee, Sch Life Sci, Wellcome Ctr Antiinfect Res, Drug Discovery Unit, Dow St, Dundee DD1 5EH, Scotland

[2] Cardiff Univ, Med Discovery Inst, Cardiff CF10 3XQ, S Glam, Wales

[3] AstraZeneca, IMED Biotech Unit, New Modal Drug Safety & Metab, SE-43183 Gothenburg, Sweden

[4] Univ Dundee, Div Mol Med, Dermatol & Genet Med, Dundee DD1 5EH, Scotland

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 03期

基金：

英国惠康基金;

关键词：

S1PR; soft-drug; plasma stability; topical tool compound; CANCER; DESIGN;

D O I：

10.1021/acsmedchemlett.8b00616

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：341 / 347

页数：13

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