Synthesis and SAR of 1,3-thiazolyl thiophene and pyridine derivatives as potent, orally active and S1P₃-sparing S1P₁ agonists
2012
Asano, Masayoshi | Nakamura, Tsuyoshi | Sekiguchi, Yukiko | Mizuno, Yumiko | Yamaguchi, Takahiro | Tamaki, Kazuhiko | Shimozato, Takaichi | Doi-Komuro, Hiromi | Kagari, Takashi | Tomisato, Wataru | Inoue, Ryotaku | Yuita, Hiroshi | Oguchi-Oshima, Keiko | Kaneko, Reina | Nara, Futoshi | Kawase, Yumi | Masubuchi, Noriko | Nakayama, Shintaro | Koga, Tetsufumi | Namba, Eiko | Nasu, Hatsumi | Nishi, Takahide
We have previously disclosed 1,2,4-oxadiazole derivative 3 as a potent S1P₃-sparing S1P₁ 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 EC₅₀ value of 3.4nM for human S1P₁, and over 5800-fold selectivity against S1P₃. In rat on host versus graft reaction (HvGR), the ID₅₀ value of 24c was determined at 0.07mg/kg. The pharmacokinetics in rat and monkey is also reported. Compared to compound 3, 24c showed excellent stability against enterobacteria.
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