title: Synthesis and SAR of 1,3-thiazolyl thiophene and pyridine derivatives as potent, orally active and S1P₃-sparing S1P₁ agonists.
abstract: We have previously disclosed 1,2,4-oxadiazole derivative 3 as a potent S1P(3)-sparing S1P(1) agonist. Although compound 3 exhibits potent and manageable immunosuppressive efficacy in various in vivo models, recent studies have revealed that its 1,2,4-oxadiazole ring is subjected to enterobacterial decomposition. As provisions for unpredictable issues, a series of alternative compounds were synthesized on the basis of compound 3. Extensive SAR studies led to the finding of 1,3-thiazole 24c with the EC(50) value of 3.4 nM for human S1P(1), and over 5800-fold selectivity against S1P(3). In rat on host versus graft reaction (HvGR), the ID(50) value of 24c was determined at 0.07 mg/kg. The pharmacokinetics in rat and monkey is also reported. Compared to compound 3, 24c showed excellent stability against enterobacteria.
authors.affiliation: Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Asano
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sekiguchi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tamaki
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: 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: Futoshi
authors.initials: F
authors.lastname: Nara
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kawase
authors.forename: Noriko
authors.initials: N
authors.lastname: Masubuchi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakayama
authors.forename: Tetsufumi
authors.initials: T
authors.lastname: Koga
authors.forename: Eiko
authors.initials: E
authors.lastname: Namba
authors.forename: Hatsumi
authors.initials: H
authors.lastname: Nasu
authors.forename: Takahide
authors.initials: T
authors.lastname: Nishi
mesh_terms: D000818:Animals; D000882:Haplorhini; D006801:Humans; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D013844:Thiazoles; D013876:Thiophenes