175277-27-7Relevant articles and documents
Synthesis and SAR of 1,3-thiazolyl thiophene and pyridine derivatives as potent, orally active and S1P3-sparing S1P1 agonists
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
scheme or table, p. 3083 - 3088 (2012/06/04)
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 3.4 nM 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 0.07 mg/kg. The pharmacokinetics in rat and monkey is also reported. Compared to compound 3, 24c showed excellent stability against enterobacteria.
