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.
Highlights
Sphingosine-1-phosphate receptor (S1PR) agonists, such as fingolimod and ponesimod (Figure 1), initially activate S1P receptors but subsequently trigger receptor internalization and downregulation of signaling; shutting down the sphingosine-1-phosphate signaling pathway
Fingolimod was approved in 2010 for the treatment of relapsing/remitting multiple sclerosis and is the only S1PR agonist approved to date.[1]
The potential for the S1PR pathway to be of therapeutic use in the treatment of a range of diverse inflammatory skin diseases has emerged.[2−6] Some studies have explored the skin biology of S1PR agonists by topical application of these compounds in various animal models of diseases such as atopic dermatitis,[4] allergic dermatitis,[5] and psoriasis.[6]
Summary
H S1PR1 pIC50a Kinetic Solubility (μM)b pKac HLM Cld H Heps Cle stabilityf CHI logDg. aHuman S1PR1 activity was measured using a human PathHunter β-Arrestin recruitment assay. All pIC50s reported in this table correspond to n ≥ 2, reported as their geometric mean. BThe aqueous kinetic solubility of the test compounds was measured using laser nephelometry: n = 1. CpKa was determined using a potentiometric fast UV-metric titration method: n = 1. DIntrinsic clearance in human liver microsomes (mL/min/g): n = 1. EIntrinsic clearance in human liver hepatocytes (mL/min/g): n = 1. F% decrease in purity when stored in DMSO solution for 28 days: n = 1. GReverse-phase HPLC method to determine the chromatographic hydrophobicity index (CHI): n = 1
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