2. Academic Validation
  3. Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist

Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist

  • ACS Med Chem Lett. 2011 Mar 2;2(5):368-72. doi: 10.1021/ml100301k.
Takahide Nishi 1,  Shojiro Miyazaki 1,  Toshiyasu Takemoto 1,  Keisuke Suzuki 1,  Yukiko Iio 1,  Katsuyoshi Nakajima 1,  Takashi Ohnuki 1,  Yumi Kawase 1,  Futoshi Nara 1,  Shinichi Inaba 1,  Takashi Izumi 1,  Hiroshi Yuita 2,  Keiko Oshima 2,  Hiromi Doi 2,  Ryotaku Inoue 2,  Wataru Tomisato 2,  Takashi Kagari 2,  Takaichi Shimozato 2
Affiliations

Affiliations

  • 1 Lead Discovery & Optimization Research Laboratories I, Cardiovascular-Metabolics Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
  • 2 Oncology Research Laboratories and Frontier Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan.
PMID: 24900318 DOI: 10.1021/ml100301k
Abstract

CS-0777 (3) is phosphorylated in vivo, and the phosphate of CS-0777 (CS-0777-P) (4) acts as a selective S1P receptor-1 (S1P1) modulator. We report herein the synthesis of CS-0777 and CS-0777-P, pharmacological effects such as S1P1 and S1P3 agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effect on experimental autoimmune encephalomyelitis (EAE), and also the pharmacokinetics in rats. CS-0777-P had ∼320-fold greater agonist activity for human S1P1 (EC50; 1.1 nM) relative to S1P3 (EC50; 350 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-0777 in rats, lymphocyte counts decreased significantly, with a nadir at 12 h postdose and recovery to vehicle control levels by 5 days postdose. In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for the 0.1 and 1 mg/kg CS-0777 groups in rats. CS-0777 is currently in clinical trials for the treatment of multiple sclerosis (MS).

Keywords

CS-0777; EAE; MS; S1P1; agonist; lymphocyte.

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