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

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

  • Bioorg Med Chem Lett. 2012 Feb 15;22(4):1788-92. doi: 10.1016/j.bmcl.2011.12.019.
Tsuyoshi Nakamura 1,  Masayoshi Asano,  Yukiko Sekiguchi,  Yumiko Mizuno,  Kazuhiko Tamaki,  Takako Kimura,  Futoshi Nara,  Yumi Kawase,  Takaichi Shimozato,  Hiromi Doi,  Takashi Kagari,  Wataru Tomisato,  Ryotaku Inoue,  Miyuki Nagasaki,  Hiroshi Yuita,  Keiko Oguchi-Oshima,  Reina Kaneko,  Nobuaki Watanabe,  Yasuyuki Abe,  Takahide Nishi
Affiliations

Affiliation

  • 1 Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan.
PMID: 22264485 DOI: 10.1016/j.bmcl.2011.12.019
Abstract

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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