The S1P1 receptor agonist FTY720 (fingolimod), as the immunomodulator, has been approved by the FDA for treating multiple sclerosis, but its S1P3 agonism may be relative to a number of side effects such as bradycardia. In our group, a series of 2-aminopropane-1, 3-diol derivatives were designed and synthesized. Extensive structure�activity relationship studies led to the discovery of SYL933, a selective S1P1 receptor agonist (prodrug). Upon phosphorylation, the compound (SYL933-P) showed nanomole S1P1 agonist activity (EC50=40.9 nM) with >30-fold selectivity over S1P3 (EC50=1273 nM). Dosed orally at 1 mg/kg in SD rats, SYL933 significantly reduced blood lymphocyte counts, which was equivalent to FTY720, but showed much less effects on heart rate than FTY720. Impressively, SYL933 showed good in vivoactivitiesin rat adjuvant induced arthritis model, rat type IIcollagen induced arthritis model, mouse EAE model and mouse psoriasis model. The PK/PD study reveals good pharmacokinetic properties of SYL933 (bioavailability: 48.6%, cumulative excretion: 37.3%, plasma protein binding: 95.09%). It was found that SYL933 was relatively stable in human/monkey/rat liver microsomes and had no obvious inhibitory effect on human CYP450s. Moreover, low Cardiac hERG toxicity of SYL933 was discovered (IC50=8.07 �M). On the basis of the favorable in vitro, in vivo activities, good PK/PD profiles as well as broad toxicology evaluations, SYL933 was considered as a promising candidate in preclinical trial.

Discovery of SYL933: A 2-aminopropane-1, 3-diol derivative as potent and selective S1P<sub>1</sub> receptor agonist (prodrug)

247th National Meeting (2014)

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Discovery of SYL933: A 2-aminopropane-1, 3-diol derivative as potent and selective S1P1 receptor agonist (prodrug)

Discovery of SYL933: A 2-aminopropane-1, 3-diol derivative as potent and selective S1P₁ receptor agonist (prodrug)