Design and Synthesis of Selective and Potent Orally Active S1P5 Agonists

Putting the brakes on demyelination: Fingolimod (FTY720) was recently shown to significantly decrease relapse rates in patients with multiple sclerosis. This drug attenuates the trafficking of harmful T‐cells entering the brain by regulating sphingosine‐1‐phosphate (S1P) receptors. We designed, synthesized, evaluated 2H‐phthalazin‐1‐one derivatives (e.g., 1 L) as selective S1P5 receptor agonists; these compounds are highly potent and selective, with good PK properties, and significant activity in oligodendrocytes.