Synthesis and evaluation of CS-2100, a potent, orally active and S1P3- sparing S1P1 agonist

Modulators of sphingosine phosphate receptor-1 (S1P1) have recently been focused as a suppressant of autoimmunity. We have discovered a 4-ethylthiophene-based S1P1 agonist 1-({4-Ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylic acid (CS-2100, 8) showing potent S1P1 agonist activity against S1P3 and an excellent in vivo potency. We report herein the synthesis of CS-2100 (8) and pharmacological effects such as S1P1 and S1P3 agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effects on adjuvant-induced arthritis and experimental autoimmune encephalomyelitis (EAE) in animal models. The pharmacokinetic data were also reported. CS-2100 (8) had >5000-fold greater agonist activity for human S1P1 (EC50; 4.0 nM) relative to S1P3 (EC50; >20000 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-2100 (8) in rats, lymphocyte counts decreased significantly, with a nadir at 8 and/or 12 h post-dose and recovery to vehicle control levels by 24–48 h post-dose. CS-2100 (8) is efficacious in the adjuvant-induced arthritis model in rats (ID50; 0.44 mg/kg). In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for 0.3 and 1 mg/kg CS-2100 (8) groups in mice. While CS-2100 (8) showed potent efficacy in various animal disease models, it was also revealed that the central 1,2,4-oxadiazole ring of CS-2100 (8) was decomposed by enterobacteria in intestine of rats and monkeys, implicating the latent concern about an external susceptibility in its metabolic process in the upcoming clinical studies.

We report the synthesis and evaluation of the sphingosine 1-phosphate receptor-1 (S1P1) agonist (CS-2100, 8). Compound 8 showed potent S1P1 agonist activity against S1P3 and an excellent in vivo potency.Figure optionsDownload as PowerPoint slideHighlights
► Synthesis of sphingosine 1-phosphate receptor-1 (S1P1) agonist (CS-2100, 8).
► Compound 8 had >5000-fold greater agonist activity for human S1P1 relative to S1P3.
► The effects of 8 on peripheral blood lymphocyte counts were investigated in rats.
► Compound 8 showed potent efficacy in several animal disease models.