clinical pipeline
Sphingosine-1-phosphate 1
(S1P1) receptor agonists
Sphingosine 1-phosphate (S1P) is a circulating phospholipid that binds to five G protein-coupled receptor (GPCR's), termed S1P1-5. One of these receptors, S1P1, is expressed on the surface of many cells including vascular endothelial cells, brain cells, and lymphocytes. Stimulation (agonism) of S1P1 selectively regulates physiological functions in the immune and cardiovascular systems, including immune cell trafficking, vascular development, and strengthening of endothelial cell-cell interactions.
Stimulation of S1P1 results in biological activities that are likely to ameliorate pathological processes associated with MS. These include:
- Lymphocyte sequestration in peripheral lymphoid organs (e.g. lymph nodes), resulting in reversible systemic lymphopenia. Since MS is considered an autoimmune-driven inflammatory disease, prevention of trafficking of disease-exacerbating, self-reactive lymphocytes to the CNS is likely to have immunomodulatory effects with a consequent dampening of disease processes.
- Enhancement of endothelial barrier function. MS is characterized by a breakdown in the vascular endothelium associated with the blood-brain barrier, resulting in easier access of proinflammatory cells (including self-reactive lymphocytes) into the brain. S1P1 receptor stimulation strengthens endothelial cell association and supports integrity of the blood-brain barrier.