Patent Watch

November 4, 2013

These sphingosine-1-phosphate modulators may be useful for treating numerous medical conditions. W. K. Fang and co-inventors describe several thiobenzyl and sulfinylbenzyl derivatives that are represented generally by formula 1 (Figure 1). These selective sphingosine-1-phosphate (S1P, 2) modulators potentially may be used to treat a variety of diseases and conditions.

General formula for S1P modulators and structure of S1P

S1P belongs to a large group of bioactive lipids that act as signaling mediators. S1P is a critical regulator of many physiological and pathophysiological processes, including cancer, cardiovascular diseases, atherosclerosis, diabetes, and osteoporosis. Five specific G protein–coupled receptors mediate most of the known actions of S1P.

S1P has important intracellular targets that are involved in inflammation, cancer, and Alzheimer’s disease. Evidence implicates S1P in the pathogenesis of age-related “wet” macular degeneration (wet AMD); inhibiting it may provide effective treatment for this disease. Other studies suggest a role for S1P in the beneficial clinical effects of high-density lipoprotein (HDL) by stimulating the production of nitric oxide. S1P may also have a role in cell division or proliferation that influence the development of cancers.

S1P activities are diverse and complex. Modulating these activities may help in the development of treatments for multiple disorders.

The compounds reported by the inventors are S1P modulators. They define the term “modulator” as “receptor agonist, antagonist, inverse agonist, inverse antagonist, partial agonist, [or] partial antagonist”.

Activities of three S1P modulators

The inventors describe the synthesis and structures of six thiobenzyl and sulfinylbenzyl compounds of formula 1, including compounds 3, 4, and 5 illustrated in Figure 2. They used the GTP Y35S binding assay to measure the S1P1 activity of the compounds. The table shows the EC50 values of the selected compounds.

Example GTP Y35S assay,
EC50 (nM)
3 81.74
4 2.65
5 0.76

(Allergan [Irvine, CA]. WIPO Publication 2013126438, Aug 29, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

View patent information from CAplus(SM) database.

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