Several S1P receptor agonists have been studied for treating relapsing-remitting multiple sclerosis (MS) and other autoimmune diseases. Immuno-modulating effect of S1P1 receptor agonists is based on reducing the number of circulating lymphocyte through agonist's binding to the S1P1 receptor on Lymphocyte then inducing internalization of the receptor via beta-arrestin signaling (functional antagonism). Though reported S1P1 agonists have shown high efficacy in clinical trials, none of them could avoid adverse effects including heart rate reduction. These unfavorable effects of S1P1 agonists are presumably caused by the stimulation of S1P1 receptor on cardiomyocytes via G-protein (Gi) signaling and sequential GIRK channel activation. We hypothesized that a novel S1P1 agonist that has sufficient receptor internalization activity via beta-arrestin signaling but with weaker GIRK activity via Gi signaling activity is expected to be a next-generation S1P1 agonist having a broader therapeutic window. In order to create the compound with our aim, we optimized our thiazole derivatives based on in vitro (receptor internalization assay and Ca influx assay) and in vivo (lymphocyte reduction and cardio-toxicity in rats) tests. One of the optimized compounds CP9531 has impressive efficacy both in vitro and vivo tests and improved safety profile. Interestingly, CP9531 and its some derivatives have a potent Ca influx activity that is distinct from other S1P1 agonists in clinical trials. We speculated that CP9531 derivatives activate not only Gi, but other G-proteins (such as Gq) that weaken the Gi signaling in the cell, and consequently moderate the cardio-toxicity derived from the S1P1 receptor stimulation by agonists. Additionally, CP9531 induced faster receptor internalization than BAF-312 (siponimod). These results indicate that our compounds are expected to have broader therapeutic window and faster onset than other S1P1 receptor agonists. Detailed SAR will be discussed in the presentation.

Novel S1P1 receptor agonists with unique intracellular signaling

246th National Meeting (2013)

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