Potency and selectivity The principle of autoimmune therapy based on targeting S1P receptors was established through the clinical work performed during development of fingolimod (trade name Gilenya), a non‐selective S1P modulator. The prospects for<unk>  (Scripps-Receptos compound RPC1063) depended upon demonstration of comparable or better activity and selectivity relative to fingolimod and other comparators. During the discovery phase of its development,<unk>  was shown to be a selective agonist of the S1P1 and S1P5 receptors. Specifically, in a discovery research report,<unk> 's equal potency and improved selectivity for S1P1 and S1P5 receptor family members were determined though a combination of inhibition, binding, and signalling assays for the S1P1, S1P2, S1P3, S1P4, and S1P5 receptor types alongside the same tests with fingolimod and other compounds. Potency for<unk>  as an agonist of the S1P1 receptor type was established through observed sub-nanomolar EC50 values in GTPγS binding and cAMP inhibition assays, and for the S1P5 type through an observed nanomolar EC50 value in the GTPγS binding assay. Measured alongside its binding to the S1P2, S1P3, and S1P4 receptor types, these concentration-response results supported a conclusion of an improved selectivity profile, with selectivity of S1P1 over S1P5 receptors at 27‐fold, and selectivity for S1P1 over S1P2, S1P3, and S1P4 receptors greater than 10,000‐fold. Also, these assays allowed comparison of<unk>  potency against and selectivity for S1P1 over other S1 receptors, relative to related S1 active agents siponimod and the phosphorylated (prodrug) forms of fingolimod and mocravimod, where<unk>  was similar to these comparators in S1P1 potency, but had the elevated selectivities stated above (versus fingolimod being potent in stimulating S1P3, S1P4, and S1P5, siponimod potent with a S1P5 form, and mocravimod active in some way against S1P3, S1P4, and S1P5), making its selectivity profile an improvement over all of these. Hence, the study concluded that it had "established... RPC1063 as a potent agonist of the S1P1 receptor with additional agonist activity on the S1P5 receptor" with S1P1 activity "similar to other known, less selective S1P receptor agonists". Pharmacodynamics and pharmacokinetics The agonism of S1P directly causes its internalization and degradation through the ubiquitin-proteosome pathway. The loss of S1P leads to a decrease in the total lymphocyte count in circulation, specifically CD4+ CCR7+ and CD8+ CCR7+ T cells.<unk>  has a high oral bioavailability, a circulating half-life of about 19 hours, and reaches highest blood plasma concentrations after about 6 hours.<unk>  is dehydrogenated by two CYP enzymes into two active metabolites, all with similar pharmacokinetics. The decrease in lymphocyte count lasts for approximately 14 days after treatment discontinuation. Unlike fingolimod, it does not require phosphorylation for activation, nor does it demonstrate cardiac abnormalities or hepatotoxicity.
Ozanimod
Siponimod
Ponesimod
Belinostat
Nusinersen
Inotersen
Calaspargase pegol
Aflibercept