Spiro-1-benzofuranpiperidinylalkanoic acids as a novel and selective sphingosine S1P5 receptor agonist chemotype

The potent and orally available S1P5 receptor agonist 32 showed high S1P5 receptor selectivities against the S1P1-3 receptor subtypes. [Display omitted] The synthesis and SAR of a novel class of spirobenzofuranpiperidinyl-derived alkanoic acids 6–34 as sphingosine S1P5 receptor agonists are described. The target compounds generally elicit high S1P5 receptor agonistic potencies and in general are selective against both S1P1 and S1P3 receptor subtypes. The key compound 32 shows a high bioavailability of 73% and a CNS/plasma ratio of 0.8 after oral administration in rats.