Discovery of CS-2100, a potent, orally active and S1P₃-sparing S1P₁ agonist
2012
Nakamura, Tsuyoshi | Asano, Masayoshi | Sekiguchi, Yukiko | Mizuno, Yumiko | Tamaki, Kazuhiko | Kimura, Takako | Nara, Futoshi | Kawase, Yumi | Shimozato, Takaichi | Doi, Hiromi | Kagari, Takashi | Tomisato, Wataru | Inoue, Ryotaku | Nagasaki, Miyuki | Yuita, Hiroshi | Oguchi-Oshima, Keiko | Kaneko, Reina | Watanabe, Nobuaki | Abe, Yasuyuki | Nishi, Takahide
S1P₃-sparing S1P₁ 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 EC₅₀ value of 4.0nM for human S1P₁ and over 5000-fold selectivity against S1P₃. The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID₅₀ value was determined at 0.407mg/kg. The docking studies of CS-2100 with the homology model of S1P₁ and S1P₃ showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P₃, not in the case of Leu276 in S1P₁. This observation gives an explanation for the excellent S1P₃-sparing characteristic of CS-2100.
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