1. Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist
- Author
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Wataru Tomisato, Keisuke Suzuki, Ryotaku Inoue, Yumi Kawase, Takashi Izumi, Keiko Oshima, Hiroshi Yuita, Takaichi Shimozato, Katsuyoshi Nakajima, Takahide Nishi, Shojiro Miyazaki, Futoshi Nara, Yukiko Iio, Takashi Kagari, Shin-ichi Inaba, Takashi Ohnuki, Toshiyasu Takemoto, and Hiromi Doi
- Subjects
Agonist ,medicine.drug_class ,business.industry ,Multiple sclerosis ,Lymphocyte ,Organic Chemistry ,Experimental autoimmune encephalomyelitis ,Pharmacology ,medicine.disease ,Biochemistry ,In vitro ,medicine.anatomical_structure ,Pharmacokinetics ,In vivo ,Peripheral blood lymphocyte ,Drug Discovery ,medicine ,business - 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).
- Published
- 2011
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