title: Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist.
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).
authors.affiliation: 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.
authors.forename: Takahide
authors.initials: T
authors.lastname: Nishi
authors.affiliation: 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.
authors.forename: Shojiro
authors.initials: S
authors.lastname: Miyazaki
authors.affiliation: 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.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Takemoto
authors.affiliation: 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.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: 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.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Iio
authors.affiliation: 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.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: 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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohnuki
authors.affiliation: 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.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kawase
authors.affiliation: 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.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nara
authors.affiliation: 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.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Inaba
authors.affiliation: 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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Oncology Research Laboratories and Frontier Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yuita
authors.affiliation: Oncology Research Laboratories and Frontier Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Oncology Research Laboratories and Frontier Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Doi
authors.affiliation: Oncology Research Laboratories and Frontier Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan.
authors.forename: Ryotaku
authors.initials: R
authors.lastname: Inoue
authors.affiliation: Oncology Research Laboratories and Frontier Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Tomisato
authors.affiliation: Oncology Research Laboratories and Frontier Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kagari
authors.affiliation: Oncology Research Laboratories and Frontier Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan.
authors.forename: Takaichi
authors.initials: T
authors.lastname: Shimozato
keywords: CS-0777; EAE; MS; S1P1; agonist; lymphocyte