title: Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist.
abstract: S1P(3)-sparing S1P(1) agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC(50) value of 4.0 nM for human S1P(1) and over 5000-fold selectivity against S1P(3). The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID(50) value was determined at 0.407mg/kg. The docking studies of CS-2100 with the homology model of S1P(1) and S1P(3) showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P(3), not in the case of Leu276 in S1P(1). This observation gives an explanation for the excellent S1P(3)-sparing characteristic of CS-2100.
authors.affiliation: Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, 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: Takako
authors.initials: T
authors.lastname: Kimura
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nara
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kawase
authors.forename: Takaichi
authors.initials: T
authors.lastname: Shimozato
authors.forename: Hiromi
authors.initials: H
authors.lastname: Doi
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: Nobuaki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Abe
authors.forename: Takahide
authors.initials: T
authors.lastname: Nishi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D055808:Drug Discovery; D006801:Humans; D007107:Immune System / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C572317:CS-2100; D007166:Immunosuppressive Agents; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; D013876:Thiophenes