title: Synthesis and evaluation of CS-2100, a potent, orally active and S1P(3)- sparing S1P(1) agonist.
abstract: Modulators of sphingosine phosphate receptor-1 (S1P(1)) have recently been focused as a suppressant of autoimmunity. We have discovered a 4-ethylthiophene-based S1P(1) agonist 1-({4-Ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylic acid (CS-2100, 8) showing potent S1P(1) agonist activity against S1P(3) and an excellent in vivo potency. We report herein the synthesis of CS-2100 (8) and pharmacological effects such as S1P(1) and S1P(3) agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effects on adjuvant-induced arthritis and experimental autoimmune encephalomyelitis (EAE) in animal models. The pharmacokinetic data were also reported. CS-2100 (8) had >5000-fold greater agonist activity for human S1P(1) (EC(50); 4.0 nM) relative to S1P(3) (EC(50); >20,000 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-2100 (8) in rats, lymphocyte counts decreased significantly, with a nadir at 8 and/or 12 h post-dose and recovery to vehicle control levels by 24-48 h post-dose. CS-2100 (8) is efficacious in the adjuvant-induced arthritis model in rats (ID(50); 0.44 mg/kg). In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for 0.3 and 1 mg/kg CS-2100 (8) groups in mice. While CS-2100 (8) showed potent efficacy in various animal disease models, it was also revealed that the central 1,2,4-oxadiazole ring of CS-2100 (8) was decomposed by enterobacteria in intestine of rats and monkeys, implicating the latent concern about an external susceptibility in its metabolic process in the upcoming clinical studies.
authors.affiliation: Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Asano
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sekiguchi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tamaki
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nara
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kawase
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yabe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.forename: Emi
authors.initials: E
authors.lastname: Kamiyama
authors.forename: Yoko
authors.initials: Y
authors.lastname: Urasaki-Kaneno
authors.forename: Takaichi
authors.initials: T
authors.lastname: Shimozato
authors.forename: Hiromi
authors.initials: H
authors.lastname: Doi-Komuro
authors.forename: Takashi
authors.initials: T
authors.lastname: Kagari
authors.forename: Wataru
authors.initials: W
authors.lastname: Tomisato
authors.forename: Ryotaku
authors.initials: R
authors.lastname: Inoue
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nagasaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yuita
authors.forename: Keiko
authors.initials: K
authors.lastname: Oguchi-Oshima
authors.forename: Reina
authors.initials: R
authors.lastname: Kaneko
authors.forename: Takahide
authors.initials: T
authors.lastname: Nishi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013876:Thiophenes / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C572317:CS-2100; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; D013876:Thiophenes