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Bioorg Med Chem Lett. 2012 Feb 15;22(4):1788-92. doi: 10.1016/j.bmcl.2011.12.019. Epub 2012 Jan 2.

Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist.

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Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan.


S1P(3)-sparing S1P(1) agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC(50) value of 4.0 nM for human S1P(1) and over 5000-fold selectivity against S1P(3). The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID(50) value was determined at 0.407mg/kg. The docking studies of CS-2100 with the homology model of S1P(1) and S1P(3) showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P(3), not in the case of Leu276 in S1P(1). This observation gives an explanation for the excellent S1P(3)-sparing characteristic of CS-2100.

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