Lipid-like sulfoxides and amine oxides as inhibitors of mast cell activation

Abstract

The drug miltefosine is a prototypic lipid-like compound thought to modulate membrane environments and thereby indirectly prevent receptor-mediated signaling events. In addition to its primary therapeutic indications in cancer and leishmaniasis, miltefosine has also been shown to block immunoglobulin E receptor-dependent mast cell activation. Miltefosine and other alkylphospholipids that are active in mast cell degranulation assays contain a positively charged nitrogen and a phosphate group that are important for activity. In addition to alkylphospholipids, ceramides are also known to act on membrane environments and inhibit mast cell activation. We have systematically searched a very large compound collection for other lipid-like inhibitors of mast cell activation. Analogs of an initially identified screening hit were synthesized and preliminary SAR information was collected, leading to the identification of sulfoxide and amine oxide containing lipid-like compounds as new inhibitors of mast cell activation. Sulfoxide and amine oxide derivatives were found to be only slightly less active than miltefosine.