CS-0777的发现：一种强效、选择性且口服活性的S1P1激动剂。
Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist.
作者信息
Nishi Takahide, Miyazaki Shojiro, Takemoto Toshiyasu, Suzuki Keisuke, Iio Yukiko, Nakajima Katsuyoshi, Ohnuki Takashi, Kawase Yumi, Nara Futoshi, Inaba Shinichi, Izumi Takashi, Yuita Hiroshi, Oshima Keiko, Doi Hiromi, Inoue Ryotaku, Tomisato Wataru, Kagari Takashi, Shimozato Takaichi
机构信息
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.
Oncology Research Laboratories and Frontier Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan.
出版信息
ACS Med Chem Lett. 2011 Mar 2;2(5):368-72. doi: 10.1021/ml100301k. eCollection 2011 May 12.
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).
CS - 0777 (3)在体内被磷酸化，CS - 0777的磷酸盐（CS - 0777 - P）（4）作为一种选择性1 -磷酸鞘氨醇受体-1（S1P1）调节剂。我们在此报告CS - 0777和CS - 0777 - P的合成、体外诸如S1P1和S1P3激动剂活性等药理作用、外周血淋巴细胞降低作用以及对实验性自身免疫性脑脊髓炎（EAE）的抑制作用，还有在大鼠体内的药代动力学。相对于S1P3（半数有效浓度EC50；350 nM），CS - 0777 - P对人S1P1（EC50；1.1 nM）的激动剂活性高约320倍。在大鼠中单次口服给予0.1和1 mg/kg的CS - 0777后，淋巴细胞计数显著下降，给药后12小时达到最低点，给药后5天恢复到溶剂对照组水平。在EAE模型中，与溶剂处理组相比，大鼠中0.1和1 mg/kg CS - 0777组的累积EAE评分显著降低。CS - 0777目前正在进行治疗多发性硬化症（MS）的临床试验。
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